Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness

Mendelian MONDO:0012190 Pathograph 18 Show in embeddings browser Epidermolysis Bullosa Simplex Hereditary Nephropathy

An autosomal recessive tetraspanin disorder caused by biallelic loss-of-function variants in CD151. CD151 is not itself a structural component of the basement membrane; it is a lateral organiser that forms very stable complexes with the laminin-binding integrins alpha-3/beta-1 and alpha-6/beta-4 and holds those receptors in a high-avidity association with their laminin ligands. Losing it therefore weakens the same class of cell-matrix adhesion in every tissue whose epithelium is anchored that way, which is why one gene produces a three-organ syndrome: skin fragility with pretibial blistering, a progressive glomerular disease running to nephrotic-range proteinuria and kidney failure, and sensorineural hearing loss. Nail dystrophy, dental and hair abnormalities, poikiloderma and oesophageal strictures are variably present, and the published probands span a wide severity range on the same class of truncating allele. The skin lesion is intraepidermal in the lower epidermis rather than a hemidesmosomal split, which is why the condition is classified as a syndromic epidermolysis bullosa simplex rather than a junctional form.

Ask OpenScientist

Ask a research question about Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
5
Pathophys.
13
Phenotypes
5
Gaps
18
Pathograph
1
Genes
3
Medical Actions
3
Models
11
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic CD151 loss-of-function alleles. Every published proband is homozygous, and all but one arose in a consanguineous or founder pedigree; no compound heterozygote has been reported. Carriers are usually asymptomatic, but the recessive label should not be read as strictly all-or-nothing: in the Saudi pedigree two heterozygous sisters had partial phenotypes - one steroid-responsive nephrotic syndrome, the other hearing impairment with low-grade proteinuria - while other heterozygous relatives were unaffected. That is one family and is recorded in `discussions` rather than asserted as a general carrier phenotype.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:38188895 SUPPORT Human Clinical
"Nephrotic syndrome (NS)-epidermolysis bullosa (EB) sensorineural deafness syndrome is an autosomal recessive rare genetic disease caused by a CD151 gene homozygous mutation on chromosome 11p15.5."
States the inheritance mode and the homozygous CD151 lesion that defines it.
PMID:15265795 SUPPORT Human Clinical
"The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140."
The founding pedigree: three affected homozygotes, consistent with recessive inheritance.
?

Discussions and Knowledge Gaps

5
Sensorineural hearing loss is consistent across CD151 probands, but the mouse null does not become deaf and no cochlear tissue from a patient or a model has been examined. Is the human deafness a direct consequence of CD151 loss in the inner ear, and if so which structure fails?
HUMAN MODEL MISMATCH OPEN cd151_cochlear_mechanism_unmodelled
Attached to
pathophysiology#Cochlear Basement Membrane Involvement
The only mechanistic statement in the literature is the founding paper's hedge that CD151 "is probably a component of the inner ear", reasoned backwards from the patients' deafness. The one model that could test it is explicitly reported as not reproducing the phenotype. So the auditory arm of this disease rests on clinical co-occurrence alone, and a reader should not take its presence in the pathograph as evidence that the mechanism is known. This is the case HUMAN_MODEL_MISMATCH exists for rather than a plain KNOWLEDGE_GAP: evidence in the model system exists and is negative.
Do heterozygous CD151 carriers have a partial phenotype? Two heterozygous sisters in one pedigree had steroid-responsive nephrotic syndrome and hearing impairment with low-grade proteinuria, while other heterozygous relatives in the same family were asymptomatic.
KNOWLEDGE GAP OPEN cd151_heterozygote_partial_phenotype
Attached to
genetic#CD151 inheritance#Autosomal recessive
A single consanguineous family cannot distinguish a genuine carrier phenotype from coincidence or from a second segregating variant, and no carrier series has been published. It matters practically, because if carriers do have low-grade proteinuria then the relatives identified during cascade testing need renal follow-up rather than reassurance. The observation is recorded here rather than curated as a phenotype so that it is not read as an established feature.
Are the epilepsy and the sweat-chloride-positive "atypical cystic fibrosis" phenotype reported in one CD151 proband part of the syndrome?
KNOWLEDGE GAP OPEN cd151_epilepsy_and_chloride_transport
Attached to
disease#Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness
The authors argue they are, on the grounds that CD151 is expressed in the nervous system and in bronchial epithelium where CFTR operates, and that an extensive workup found no alternative cause. That argument is from tissue expression, not from any demonstrated mechanism, and it rests on one patient. Until a second proband is reported with either feature it cannot be distinguished from comorbidity in a consanguineous pedigree, so neither is curated as a phenotype of this disorder.
Where does the skin split in CD151 disease - intraepidermally, or below the epidermis? The two ultrastructural reports disagree.
CONTROVERSY OPEN cd151_cleavage_plane_unsettled
Attached to
pathophysiology#Keratinocyte Dysadhesion in the Lower Epidermis
This matters more than an ultrastructural detail normally would, because the cleavage plane is what classifies an epidermolysis bullosa subtype, and it is the organising axis of the `dermal_epidermal_junction_adhesion_failure` module this entry conforms to. PMID:29138120 examined the proband's skin by transmission electron microscopy and reports intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis - an intraepidermal plane, which is what classifies the disease as an EB simplex. PMID:35519797 reports biopsies showing subepidermal separation in its patient, though it notes that neither immunofluorescence mapping nor transmission electron microscopy was available there, so the two observations are not of equal technical weight. Cell biology favours the intraepidermal reading: PMID:31488507 shows that keratin-anchored hemidesmosomes form and persist without CD151, so the hemidesmosomal plane should not be the one that fails. But that is an argument from a cell line, not a second patient biopsy. Consequence for this entry: conformance to the module is declared at the attachment-defect and loss-of-adhesive-integrity nodes, which hold on either reading, and deliberately not at its dermal-epidermal separation node. Settling it needs immunofluorescence mapping or electron microscopy on a further proband.
What determines whether a CD151-null individual reaches end-stage kidney disease in adolescence or carries an incidental proteinuria into adulthood?
KNOWLEDGE GAP OPEN cd151_renal_severity_modifiers_unknown
Attached to
pathophysiology#Glomerular Basement Membrane Disorganization phenotypes#Stage 5 chronic kidney disease
The renal course is the most variable thing about this disease and nothing explains the variance. All three probands in the founding pedigree reached end-stage kidney disease; a later proband's renal involvement was an incidental dipstick finding, on a comparably truncating allele. Allele severity therefore does not obviously predict outcome. The mouse says the missing factor is at least partly extrinsic to CD151. The same null allele produces early massive proteinuria and kidney failure on an FVB background and essentially no spontaneous kidney phenotype on C57BL/6, and the resistant background becomes susceptible once blood and transcapillary filtration pressure are raised. So there is a genetic modifier acting somewhere, and a haemodynamic gate on top of it, and in humans neither has been identified. This is a knowledge gap rather than a controversy: nobody has proposed competing answers, because the cohort needed to look for one does not exist. It is recorded because it bears directly on management - if filtration pressure is the gate, the case for early and sustained RAAS blockade in an asymptomatic CD151 patient is stronger than the single reported human drug response can establish on its own.
Show evidence (2 references)
PMID:22201679 SUPPORT PRIMARY RESULT Model Organism
"Although global Cd151-null B6 mice were not susceptible to renal disease, as has been shown previously, increasing blood and transcapillary filtration pressure induced nephropathy in these mice."
Establishes both halves of the gap: a strain-dependent modifier, and filtration pressure as a gate on the same lesion.
PMID:38188895 SUPPORT Human Clinical
"A 13-year-old boy was brought by his mother to the emergency room in February 2019 with a history of incidental finding of proteinuria 6 months earlier, when the mother had tested his urine using a urine dipstick test at home."
The human end of the same variance: a CD151 proband whose renal disease was asymptomatic and found incidentally, against a founding pedigree that all reached end-stage disease.
⚙

Pathophysiology

5
CD151 Loss of Function
Biallelic CD151 alleles that truncate the protein before or within its large extracellular loop. The reported lesions are a frameshifting single-nucleotide insertion stopping translation at codon 140, a donor splice-site change that removes the whole of exon 5, and the nonsense alleles p.Gln136* and p.Arg165*. What they have in common is loss of the integrin-binding region, so the resulting protein cannot perform the one function CD151 has in this disease.
CD151 hgnc:1630 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CD151 (hgnc:1630). hgnc:1630 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context CD151 hgnc:1630 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CD151 (hgnc:1630). hgnc:1630 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
All published alleles are truncating and homozygous. No missense or hypomorphic allele has been reported, so there is no allelic series here to grade severity against.
Downstream
Destabilization of Laminin-Binding Integrin Adhesion Complexes Without the integrin-binding region there is no lateral organiser to hold the laminin-binding integrins in their high-avidity state.
Show evidence (2 references)
PMID:15265795 SUPPORT DIRECT Human Clinical
"The resultant truncated protein would lack its integrin-binding domain."
Names the specific functional consequence of the founding allele: loss of the region through which CD151 binds its integrin partners.
PMID:29138120 SUPPORT DIRECT Human Clinical
"Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151."
Demonstrates at protein level that the splice allele produces a null, not a reduced-function product.
Destabilization of Laminin-Binding Integrin Adhesion Complexes
CD151 normally clusters integrin alpha-3/beta-1 and alpha-6/beta-4 laterally and stabilises their engagement with laminin in the underlying basement membrane. In its absence the receptors are still expressed but the adhesion they mediate is weaker and less persistent. This single molecular failure is what makes the disorder multi-organ: the same integrin-laminin axis anchors basal keratinocytes to laminin-332 in skin and podocytes to laminin-521 in the glomerulus.
integrin-mediated cell-matrix adhesion GO:0033627 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased integrin-mediated cell-matrix adhesion, annotated with cell adhesion mediated by integrin (GO:0033627). GO:0033627 is a biological process from the Gene Ontology. ↓ DECREASED
laminin binding by the CD151-integrin complex GO:0043236 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased laminin binding by the CD151-integrin complex, annotated with laminin binding (GO:0043236). GO:0043236 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Keratinocyte Dysadhesion in the Lower Epidermis Loss of the stabilised adhesion in basal and immediately suprabasal keratinocytes.
Glomerular Basement Membrane Disorganization Loss of podocyte-GBM adhesion under the mechanical load of filtration, with secondary structural change in the membrane itself.
Cochlear Basement Membrane Involvement The inner-ear arm. Note the founding paper states this as an inference from the clinical phenotype rather than from direct cochlear study.
Show evidence (3 references)
PMID:31488507 SUPPORT DIRECT In Vitro
"We show that CD151, through binding to integrin α3β1, plays a critical role in the stabilization of an adhesion structure with a distinct molecular composition of hemidesmosomes with tetraspanin features."
Direct cell-biological demonstration that CD151 works by stabilising a laminin-binding integrin adhesion, which is the lesion this node asserts.
PMID:35278129 SUPPORT DIRECT BACKGROUND Other
"CD151 interacts with the laminin–integrin–actin axis, specifically via integrin α3β1, increasing the strength of integrin-dependent adhesion of the podocyte to laminin-521 in the GBM."
States the same mechanism on the renal side, naming the specific laminin isoform the podocyte binds.
PMID:32667818 SUPPORT DIRECT REVIEW SYNTHESIS Other
"CD151 regulates interactions with laminin-binding integrins α3β1, α6β1, α6β4, and α7β1 and is expressed on red blood cells as well as many other tissues and cancer types."
Gives the full laminin-binding partner set, which is wider than the two partners this node names and wider than the three organs the disease affects. That mismatch is the tissue-selectivity question recorded in the discussions, not an omission here.
Keratinocyte Dysadhesion in the Lower Epidermis
Basal and lower-epidermal keratinocytes separate from one another and from the matrix under minor mechanical stress. The split is intraepidermal, which is what classifies this as an epidermolysis bullosa simplex rather than a junctional form, and it sits alongside intact keratin-anchored hemidesmosomes - cell-biology work shows those form and persist without CD151.
basal keratinocyte of the epidermis CL:0002187 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves basal keratinocyte of the epidermis, annotated with basal cell of epidermis (CL:0002187). CL:0002187 is a cell type from the Cell Ontology.
keratinocyte cell-matrix adhesion GO:0007160 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased keratinocyte cell-matrix adhesion, annotated with cell-matrix adhesion (GO:0007160). GO:0007160 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Pretibial blistering The clinical blistering that follows loss of keratinocyte adhesion.
Show evidence (2 references)
PMID:29138120 SUPPORT DIRECT Human Clinical
"Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis."
Ultrastructural evidence from patient skin for the cellular lesion this node names.
PMID:31488507 SUPPORT DIRECT In Vitro
"In contrast, hemidesmosomes, keratin filament-associated adhesions that contain integrin α6β4, plectin, BP180 (encoded by COL17A1) and BP230 (encoded by DST), do not require CD151 for their formation or maintenance."
Explains why the cleavage plane is intraepidermal rather than at the hemidesmosome: CD151 is not needed to build a hemidesmosome.
Glomerular Basement Membrane Disorganization
Podocyte attachment to the glomerular basement membrane is under continuous mechanical load during filtration, so a weakened integrin-laminin bond has structural consequences here that it does not have in quieter tissues. Patient biopsies show a thickened, disorganised GBM with podocyte foot-process effacement - the classical substrate of a glomerular protein leak.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
basement membrane organization GO:0071711 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased basement membrane organization (GO:0071711). GO:0071711 is a biological process from the Gene Ontology. ↓ DECREASED
glomerular basement membrane UBERON:0005777 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in glomerular basement membrane (UBERON:0005777). UBERON:0005777 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Cd151-null mouse Mouse partially recapitulates Reproduces the renal arm on a permissive background, including the FSGS endpoint seen in patients.
Podocyte-specific Cd151 conditional knockout mouse Mouse recapitulates Podocyte-restricted deletion reproduces the glomerular lesion, isolating the podocyte as the cell in which the CD151 requirement is non-redundant.
Downstream
Nephrotic range proteinuria Filtration-barrier failure following podocyte detachment and GBM disorganization.
Thickened glomerular basement membrane The membrane lesion itself as it appears on electron microscopy. This is the node's own structural readout rather than a downstream consequence of it, and is wired so the ultrastructural findings sit in the graph rather than beside it.
Podocyte foot process effacement The podocyte-side readout of the same failed attachment, seen on the same biopsies. Effacement follows loss of the integrin-laminin anchorage that holds the foot processes against the membrane.
Focal segmental glomerulosclerosis The sclerosing response that follows sustained podocyte loss.
Show evidence (3 references)
PMID:35278129 SUPPORT DIRECT Human Clinical
"Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
Direct ultrastructural observation in a CD151 patient of the tissue lesion this node asserts.
PMID:22338088 SUPPORT INDIRECT In Vitro
"CD151 knockdown in podocytes reduced β(1)-integrin expression and podocyte cell area, indicating diminished adherence and/or spreading."
Gives the cellular mechanism behind the tissue lesion. INDIRECT because it is a knockdown in a mouse podocyte line, not the patient's glomerulus.
PMID:22201679 SUPPORT INDIRECT Model Organism
"Although global Cd151-null B6 mice were not susceptible to renal disease, as has been shown previously, increasing blood and transcapillary filtration pressure induced nephropathy in these mice."
Evidence for the mechanical-load premise this node rests on: the same null allele is silent in the kidney until filtration pressure is raised, so it is the load across the adhesion rather than the loss of CD151 alone that produces the lesion. INDIRECT because it is a mouse experiment standing in for the human glomerulus.
Cochlear Basement Membrane Involvement
The least directly evidenced arm of the disease. Sensorineural hearing loss is consistent across probands, and CD151 is inferred to be a component of the inner ear, but no human or model cochlear tissue study has been reported, and the Cd151 knockout mouse does not reproduce the deafness. This node is curated because the phenotype is consistent and needs somewhere to attach, not because the mechanism is established.
cochlea UBERON:0001844 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cochlea (UBERON:0001844). UBERON:0001844 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Cd151-null mouse Mouse fails to recapitulate The mouse null is deliberately recorded as a negative for the extrarenal arms. This is the structural reason the auditory mechanism in this disease is unresolved rather than merely uninvestigated.
Downstream
Sensorineural hearing impairment The clinical auditory phenotype.
Show evidence (2 references)
PMID:15265795 SUPPORT INDIRECT Human Clinical
"is probably a component of the inner ear"
The only mechanistic statement in the literature about the auditory arm, and the authors hedge it.
PMID:35278129 REFUTE DIRECT REVIEW SYNTHESIS Model Organism
"The extrarenal features, including sensorineural deafness and bullous skin lesions, have not been replicated in knockout mouse models"
Records that the mouse null does not reproduce the deafness, which refutes any claim that the auditory arm is a settled, model-supported mechanism. REVIEW_SYNTHESIS because this review is summarising the model literature rather than reporting its own knockout.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Digestive 1
Esophageal stricture HP:0002043 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esophageal stricture (HP:0002043). HP:0002043 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29138120 SUPPORT Human Clinical
"revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
Oesophageal webbing and strictures in the Iranian proband.
PMID:35519797 SUPPORT Human Clinical
"She also has a history of sensorineural hearing loss and is followed by a gastrointestinal specialist for dysphagia with small esophageal strictures."
Independent report of oesophageal strictures with dysphagia.
Ear 1
Sensorineural hearing impairment FREQUENT HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15265795 SUPPORT Human Clinical
"In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor."
Sensorineural deafness in the founding pedigree.
PMID:35519797 SUPPORT Human Clinical
"She also has a history of sensorineural hearing loss and is followed by a gastrointestinal specialist for dysphagia with small esophageal strictures."
Independent confirmation in a separately ascertained proband.
Genitourinary 5
Nephrotic range proteinuria VERY_FREQUENT HP:0012593 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic range proteinuria (HP:0012593). HP:0012593 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35278129 SUPPORT Human Clinical
"We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria."
Nephrotic-range proteinuria in a genetically confirmed CD151 patient.
PMID:38188895 SUPPORT Human Clinical
"In this report, we discuss a rare case related to a Saudi patient with genetic syndrome who presented with NS and EB."
An independent proband presenting with nephrotic syndrome alongside the skin disease.
Focal segmental glomerulosclerosis HP:0000097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal segmental glomerulosclerosis (HP:0000097). HP:0000097 is a phenotype from the Human Phenotype Ontology.
Sequelae: Stage 5 chronic kidney disease
Show evidence (1 reference)
PMID:35519797 SUPPORT Human Clinical
"chronic kidney disease secondary to nephrotic syndrome from focal segmental glomerular sclerosis"
Names FSGS as this proband's renal histology.
Podocyte foot process effacement HP:0031266 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Podocyte foot process effacement (HP:0031266). HP:0031266 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35278129 SUPPORT Human Clinical
"Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
Direct electron-microscopy observation of foot-process effacement in a CD151 patient.
Thickened glomerular basement membrane HP:0004722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thickened glomerular basement membrane (HP:0004722). HP:0004722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35278129 SUPPORT Human Clinical
"Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
The same observation, curated here for the membrane finding specifically.
Stage 5 chronic kidney disease HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15265795 SUPPORT Human Clinical
"We examined CD151 in 3 MER2-negative patients (2 are sibs) of Indian Jewish origin with end-stage kidney disease."
End-stage kidney disease in all three founding probands.
PMID:38188895 SUPPORT BACKGROUND Human Clinical
"This syndrome is reported to have an adolescent age of onset and is characterized by hereditary nephritis, leading to NS and ESRD, associated with sensorineural hearing loss and pretibial skin blistering [Table 1].[2]"
Restates progression to end-stage renal disease as part of the established clinical description. Marked BACKGROUND because this case report is summarising prior reports here, not its own result.
Head and Neck 2
Premature loss of permanent teeth HP:0006357 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature loss of permanent teeth (HP:0006357). HP:0006357 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29138120 SUPPORT Human Clinical
"revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
Loss of teeth in the Iranian proband.
Enamel hypoplasia HP:0006297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enamel hypoplasia (HP:0006297). HP:0006297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35519797 SUPPORT Human Clinical
"Onychodystrophy and dental enamel hypoplasia as well as scattered poikiloderma and patchy alopecia were also diagnosed."
Enamel hypoplasia on examination of the fifth reported proband.
Integument 4
Pretibial blistering VERY_FREQUENT HP:0012221 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pretibial blistering (HP:0012221). HP:0012221 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15265795 SUPPORT Human Clinical
"In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor."
Pretibial blistering in the founding pedigree.
PMID:35519797 SUPPORT Human Clinical
"she demonstrated linear pretibial and upper extremity extensor bullae on minimally erythematous bases"
The examination finding in an independently ascertained proband, with the same pretibial and extensor distribution.
Nail dystrophy HP:0008404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dystrophy (HP:0008404). HP:0008404 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29138120 SUPPORT Human Clinical
"revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
Nail dystrophy in the examination of the Iranian proband.
PMID:35278129 SUPPORT Human Clinical
"We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria."
Nail dystrophy as a presenting feature in an independent proband.
Poikiloderma HP:0001029 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poikiloderma (HP:0001029). HP:0001029 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29138120 SUPPORT Human Clinical
"Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma"
Poikiloderma on examination, and the reason the Kindler misdiagnosis was made.
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29138120 SUPPORT Human Clinical
"revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
Early-onset alopecia in the Iranian proband.
🧬

Genetic Associations

1
CD151 (Biallelic truncating alleles (frameshift, nonsense, and a donor splice-site allele deleting exon 5))
Gene: CD151 hgnc:1630 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD151 (hgnc:1630). hgnc:1630 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (3 references)
PMID:15265795 SUPPORT Human Clinical
"The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140."
Establishes CD151 as the causative gene and gives the founding truncating allele.
PMID:29138120 SUPPORT Human Clinical
"In one family, a homozygous donor splice site mutation in CD151 (NM_139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids."
An independent allele class - a splice-site change causing exon skipping - confirming the gene in a second family.
PMID:38188895 SUPPORT Human Clinical
"Whole genome sequencing results indicated a homozygous pathogenic variant identified in the CD151 gene (c.493C>T p.(Arg165*), which was consistent with a genetic diagnosis of autosomal recessive nephropathy with pretibial EB and deafness syndrome."
A third independent family and a third truncating allele.
💊

Medical Actions

3
Renin-Angiotensin System Blockade
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: lisinopril CHEBI:43755 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lisinopril (CHEBI:43755). CHEBI:43755 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An oral ACE inhibitor is the reported pharmacological management of the proteinuria. In the one patient followed longitudinally, proteinuria resolved and then relapsed in step with adherence to lisinopril, which is about as close to a within-patient control as this literature offers. The proposed mechanism - lowering intraglomerular pressure and so the mechanical load on an adhesion-compromised capillary wall - fits the pathophysiology directly, and is supported in the Cd151-null mouse.
Mechanism Target:
Glomerular Basement Membrane Disorganization — Reduces intraglomerular pressure, lowering the mechanical demand on a podocyte-GBM attachment that CD151 loss has already weakened.
Show evidence (1 reference)
PMID:35278129 SUPPORT INDIRECT Model Organism
"This was alleviated with angiotensin-converting enzyme inhibitors, which may act by reducing the mechanical load on the capillary wall by decreasing intraglomerular pressure [9, 10]."
Gives the proposed mechanism and the mouse result behind it. INDIRECT and MODEL_ORGANISM because the observation is in Cd151-knockout mice, and the mechanism is offered as a possibility by the authors.
Show evidence (2 references)
PMID:38188895 SUPPORT DIRECT Human Clinical
"The patient had relapses of proteinuria that are most likely explained by poor compliance with Lisinopril."
Proteinuria tracking adherence in a CD151 patient is the strongest human evidence available that the drug is doing something here.
PMID:38188895 SUPPORT DIRECT Human Clinical
"He was kept on PO Lisinopril with follow-up visits."
Records the specific agent and route used in long-term management.
Wound Care and Withdrawal of Immunosuppression
Action: wound care managementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is wound care management (NCIT:C116681). NCIT:C116681 is a clinical intervention from the NCI Thesaurus. Ontology label: Wound Care Management NCIT:C116681
Platform: Behavioral / lifestyle
Skin management is non-adherent dressings, protection and nutrition. The substantive therapeutic finding in this disease is a negative one: because the blistering is often mistaken for an acquired autoimmune blistering disease, patients are treated with immunosuppressants that cannot work on a structural adhesion defect. One proband had years of topical and systemic corticosteroids, minocycline, nicotinamide, mycophenolate mofetil and methotrexate with no benefit, and improved substantially once they were all withdrawn in favour of skin care. Stopping the wrong treatment is the actionable consequence of making the genetic diagnosis.
Mechanism Target:
Keratinocyte Dysadhesion in the Lower Epidermis — Protective and mechanical, not mechanistic: dressings reduce the shear that separates keratinocytes, they do not restore the adhesion complex.
Show evidence (1 reference)
PMID:35519797 SUPPORT INDIRECT Human Clinical
"The blisters substantially improved with this regimen, and she was referred to a multidisciplinary EB clinic for further evaluation and treatment."
Records improvement on skin care after immunosuppression was withdrawn. INDIRECT for the mechanism: an uncontrolled single-patient observation with two simultaneous changes.
Show evidence (2 references)
PMID:35519797 SUPPORT DIRECT Human Clinical
"She was tapered off of all forms of immunosuppressants, with a care plan that was shifted to careful skin care, nutrition, and ocular health."
The management change itself: immunosuppression withdrawn, supportive skin care substituted.
PMID:35519797 SUPPORT DIRECT Human Clinical
"She had trialed topical corticosteroids, minocycline, nicotinamide, mycophenolate mofetil, methotrexate, and protracted courses of systemic corticosteroids with negligible therapeutic benefit prior to this visit."
Documents the failed immunosuppressive regimens, which is what makes withdrawal the right move rather than merely a neutral one.
Renal Replacement Therapy
Action: peritoneal dialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is peritoneal dialysis, annotated with Dialysis (NCIT:C15221). NCIT:C15221 is a clinical intervention from the NCI Thesaurus. Ontology label: Dialysis NCIT:C15221
Platform: Device
Dialysis for those who reach end-stage kidney disease. Peritoneal dialysis is what is recorded for the founding siblings. No transplant outcome has been reported in a CD151 patient - `CD151 AND kidney transplantation` returns nothing in PubMed, and `epidermolysis bullosa nephropathy deafness transplant` returns only PMID:28615054, which is a different gene. So nothing is asserted here about whether the disease recurs in a graft, which, given that the lesion is in the recipient's podocytes and not circulating, would be worth knowing. The nearest evidence is that case report, and it is worth carrying because the gene it names sits on the other side of the same adhesion: a woman with laminin-5 epidermolysis bullosa, bilateral sensorineural deafness and oesophageal stenosis who reached end-stage renal disease, in whom transplantation was pursued after dialysis access proved difficult. Its authors conclude that no modality should be ruled out in epidermolysis bullosa. That is a statement about EB as a group rather than about CD151, and it is recorded as such.
Show evidence (3 references)
PMID:38188895 SUPPORT DIRECT BACKGROUND Human Clinical
"Both siblings had hereditary nephritis, pre-tibial EB, and beta-thalassemia minor with nephrotic range proteinuria and ESRD and were on peritoneal dialysis."
The only record of renal replacement therapy in this disorder. Marked BACKGROUND: the citing case report is restating the earlier pedigree's course, not reporting its own.
PMID:28615054 SUPPORT INDIRECT Human Clinical
"There should be no limitations in renal replacement therapy in patients with epidermolysis bullosa."
The nearest available statement on renal replacement therapy in this disease group. INDIRECT because the reported patient has laminin-5 epidermolysis bullosa rather than a CD151 defect - the conclusion is about epidermolysis bullosa as a group, and is carried here as context, not as a CD151 finding.
PMID:28615054 SUPPORT INDIRECT Human Clinical
"There have been few reports concerning ESRD in this specific group of patients in the available literature."
Records how thin the evidence base is for renal replacement therapy across epidermolysis bullosa at all, which is why the CD151-specific negative is unsurprising rather than suspicious.
🔬

Diagnosis

3
Molecular Genetic Testing
The diagnosis is molecular. In practice it has been reached by an epidermolysis-bullosa gene panel, by targeted next-generation sequencing from a nephrology direction, and by whole genome sequencing - which route depends entirely on which specialty the patient reaches first. That is the core diagnostic problem in this disease: dermatology, nephrology and audiology each see a plausible isolated condition.
next-generation sequencing gene panel NCIT:C101293 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:29138120 SUPPORT Human Clinical
"We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction."
The skin-fragility panel route to the diagnosis.
PMID:35278129 SUPPORT Human Clinical
"Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria."
States the diagnostic gap from the nephrology side, which is why proteinuric patients are missed.
MER2 Blood Group Phenotyping
CD151 carries the MER2 antigen, so loss of CD151 makes red cells MER2-negative. Absent immunoreactivity to anti-CD151/MER2 on patient erythrocytes has been used as a confirmatory assay, and MER2-negativity is what identified the founding family in the first place. It is a cheap orthogonal check on a novel variant.
MER2/CD151 erythrocyte antigen phenotyping NCIT:C210738 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:35278129 SUPPORT Human Clinical
"Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells."
Records the MER2 red-cell assay being used as a confirmatory test in a patient.
PMID:15265795 SUPPORT Human Clinical
"We show that CD151 expresses the MER2 blood group antigen and is located on erythrocytes."
Establishes the biological basis of the blood-group test.
PMID:32667818 SUPPORT REVIEW SYNTHESIS Other
"Lack of the RAPH protein is associated with nephropathy with pretibial epidermolysis bullosa and deafness."
The blood-group literature's own statement of the association, placing MER2-negativity as a marker for this disease rather than an incidental type.
Audiological Assessment and Surveillance
The hearing loss is sensorineural, bilateral and part of the defining triad, so audiology is one of the three specialties a CD151 patient needs referred to alongside nephrology and haematology. The literature supports the referral and the surveillance; it does not describe a device, a fitting or an outcome in any reported proband, which is why no hearing treatment is asserted in this entry.
diagnostic audiology testing NCIT:C217379 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35519797 SUPPORT DIRECT Human Clinical
"In the case of CD151 defects, urinalysis, renal ultrasound, and complete blood count should be considered, as well as referrals to nephrology, hematology, and audiology specialists."
A CD151-specific workup recommendation that names audiology referral explicitly.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population-based prevalence or incidence estimate exists. The literature is a small number of case reports: PMID:35519797 describes its patient as "the fifth recorded case of EBS with nephropathy in relation to CD151 defects", and PMID:38188895 and PMID:35278129 add further probands after that. The count is recorded as a literature count rather than converted into a rate, because no denominator is available.
Show evidence (2 references)
PMID:35519797 SUPPORT Human Clinical
"This is the fifth recorded case of EBS with nephropathy in relation to CD151 defects and, to our knowledge, the first case to be reported with neurologic and chloride transport complications."
The only published count of reported cases, and the basis for the ULTRA_RARE band.
PMID:38188895 SUPPORT Human Clinical
"Nephrotic syndrome (NS)-epidermolysis bullosa (EB) sensorineural deafness syndrome is an autosomal recessive rare genetic disease caused by a CD151 gene homozygous mutation on chromosome 11p15.5."
Characterises the condition as rare; supports the band without supplying a rate.
⚖️

Clinical Burden

Variable
The renal arm dominates prognosis and is what makes the burden variable rather than uniformly high. All three probands in the founding pedigree reached end-stage kidney disease and two were on peritoneal dialysis; the Saudi proband reported eighteen years later had proteinuria detected incidentally at home and was managed on an oral ACE inhibitor. The skin disease is a lifelong dressing and wound-care burden but is not by itself life-limiting. Nothing in the cited sources characterises survival for the condition as a whole, so no mortality claim is made.
Show evidence (2 references)
PMID:38188895 SUPPORT BACKGROUND Human Clinical
"Both siblings had hereditary nephritis, pre-tibial EB, and beta-thalassemia minor with nephrotic range proteinuria and ESRD and were on peritoneal dialysis."
The severe end of the range - dialysis-dependent renal failure. Marked BACKGROUND because this case report is summarising the earlier pedigree, not its own patient.
PMID:38188895 SUPPORT Human Clinical
"The findings emphasize that even a single genotype can result in variable phenotypic expression, necessitating the assessment of the pleiotropic effects of the disease on the patient, which can range from severe to mild."
The authors' own statement that severity ranges from severe to mild, which is what VARIABLE encodes.
🐁

Animal Models

3
Cd151-null mouse
The mammalian null. Its behaviour is strain-dependent in a way that matters for interpretation: on the FVB background it develops early massive proteinuria with focal segmental glomerulosclerosis and kidney failure, while on C57BL/6 there is no spontaneous kidney phenotype at all and proteinuria appears only with hypertension. Neither background reproduces the deafness or the skin blistering.
Species
Mouse
Genotype
Cd151 global knockout
Publication
PMID:17015618
Pathograph links
Glomerular Basement Membrane Disorganization partially recapitulates fidelity: moderate observes: tissue Reproduces the renal arm on a permissive background, including the FSGS endpoint seen in patients.
Limitations: The phenotype depends on strain background rather than on the lesion, so the model reports genetic modifiers as much as it reports CD151. It also covers only one of the three affected organs.
Show evidence (2 references)
PMID:17015618 SUPPORT PRIMARY RESULT Model Organism
"We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation."
The report that generated this model, stating the renal phenotype it reproduces.
+ 1 more reference
Cochlear Basement Membrane Involvement fails to recapitulate fidelity: low observes: organism The mouse null is deliberately recorded as a negative for the extrarenal arms. This is the structural reason the auditory mechanism in this disease is unresolved rather than merely uninvestigated.
Limitations: Neither the sensorineural deafness nor the bullous skin disease appears in the knockout on any reported background, so the model cannot be used to study either arm, and the human inner-ear claim has no model support.
Show evidence (2 references)
PMID:17015618 REFUTE PRIMARY RESULT Model Organism
"However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice."
The originating report's own explicit negative for both extrarenal arms, stated in the same sentence as the renal positive.
+ 1 more reference
Podocyte-specific Cd151 conditional knockout mouse
The cell-autonomy test. Deleting Cd151 only in podocytes is sufficient to produce glomerular nephropathy, which is what licenses this entry to place the renal lesion at the podocyte rather than at the endothelium or the mesangium. The same study is also where the mechanical-load gate comes from: the global null on a resistant background stays well until filtration pressure is raised, and ACE inhibition on a susceptible background extends life span.
Species
Mouse
Genotype
Podocyte-restricted conditional Cd151 deletion
Publication
PMID:22201679
Pathograph links
Glomerular Basement Membrane Disorganization recapitulates fidelity: moderate observes: tissue Podocyte-restricted deletion reproduces the glomerular lesion, isolating the podocyte as the cell in which the CD151 requirement is non-redundant.
Limitations: Covers the renal arm only, and a conditional allele cannot speak to whether the skin and cochlear arms are likewise cell-autonomous.
Readouts
Median life span under ACE inhibition
Direction: RESTORED
Interpretation: Pharmacological reduction of filtration pressure partially rescues the outcome, which is the model-side counterpart of the RAAS-blockade management this entry records as standard of care.
Show evidence (1 reference)
PMID:22201679 SUPPORT PRIMARY RESULT Model Organism
"Importantly, blocking the angiotensin-converting enzyme in renal disease-susceptible global Cd151-null FVB mice prolonged their median life span."
The measured rescue arm behind the nephroprotection rationale.
Show evidence (1 reference)
PMID:22201679 SUPPORT PRIMARY RESULT Model Organism
"Moreover, in vivo podocyte-specific deletion of Cd151 led to glomerular nephropathy."
Establishes that loss of CD151 in the podocyte alone is sufficient for the renal phenotype.
cd151 CRISPR-depleted zebrafish
The functional assay that upgraded a novel human truncating variant from uncertain to disease-causing. Depletion produces proteinuria; wild-type human CD151 mRNA rescues it and mRNA carrying the patient variant does not, which is an allele-specific test rather than a general knockdown phenotype.
Species
Zebrafish
Genotype
CRISPR-Cas9 cd151 depletion, with wild-type and variant CD151 mRNA rescue arms
Publication
PMID:35278129
{ }

Source YAML

click to show 
name: Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness
creation_date: "2026-09-21T00:00:00Z"
description: >-
  An autosomal recessive tetraspanin disorder caused by biallelic loss-of-function
  variants in CD151. CD151 is not itself a structural component of the basement
  membrane; it is a lateral organiser that forms very stable complexes with the
  laminin-binding integrins alpha-3/beta-1 and alpha-6/beta-4 and holds those
  receptors in a high-avidity association with their laminin ligands. Losing it
  therefore weakens the same class of cell-matrix adhesion in every tissue whose
  epithelium is anchored that way, which is why one gene produces a three-organ
  syndrome: skin fragility with pretibial blistering, a progressive glomerular
  disease running to nephrotic-range proteinuria and kidney failure, and
  sensorineural hearing loss. Nail dystrophy, dental and hair abnormalities,
  poikiloderma and oesophageal strictures are variably present, and the published
  probands span a wide severity range on the same class of truncating allele.
  The skin lesion is intraepidermal in the lower epidermis rather than a
  hemidesmosomal split, which is why the condition is classified as a syndromic
  epidermolysis bullosa simplex rather than a junctional form.
category: Mendelian
parents:
- Epidermolysis Bullosa Simplex
- Hereditary Nephropathy
disease_term:
  preferred_term: epidermolysis bullosa simplex 7, with nephropathy and deafness
  term:
    id: MONDO:0012190
    label: epidermolysis bullosa simplex 7, with nephropathy and deafness
synonyms:
- EBS7
- nephropathy with pretibial epidermolysis bullosa and deafness
- nephrotic syndrome - deafness - pretibial epidermolysis bullosa syndrome
- CD151 deficiency
- CD151-associated syndromic epidermolysis bullosa simplex
notes: >-
  Entry scope. This entry curates the CD151-related syndrome as a single DISEASE.
  The stub recorded no MONDO descendants, and MONDO carries one causal gene
  relation for MONDO:0012190, to hgnc:1630 CD151 (read from
  stubs/Epidermolysis_Bullosa_Simplex_7_With_Nephropathy_And_Deafness.yaml, which
  `just enrich-stubs` wrote from MONDO). All published probands carry biallelic
  CD151 alleles and share the skin/kidney/inner-ear triad, so there is one
  conserved pathograph here and no case for a GROUPING. No `has_subtypes` rows are
  declared: the reported allele classes are all truncating (frameshift, nonsense
  and a whole-exon-skipping splice allele) and the phenotypic differences between
  probands do not track allele class, so a subtype split would assert a structure
  the literature does not support.

  Severity is genuinely uncoupled from genotype here and that is worth stating
  rather than smoothing over. PMID:38188895 reports a proband homozygous for
  p.Arg165* whose renal disease was detected incidentally on a home dipstick,
  and makes the point explicitly that one genotype gives variable expression;
  PMID:15265795 reports end-stage kidney disease in all three of its probands.
  Both are recorded, and no severity ordering is asserted between them.

  Module conformance: two modules, one per organ arm, plus a correction.

  An earlier draft of this note claimed a module search had been run and had found
  only `podocyte_injury_and_glomerular_filtration_barrier_failure` and
  `epithelial_barrier_dysfunction`. That was false in a way worth recording: no
  module of the first name exists in `kb/modules/` at all, and the real candidates
  were missed. The automated second-opinion comment on the claim issue
  (dismech#12389) named `dermal_epidermal_junction_adhesion_failure` and
  `nephrotic_podocyte_injury`; `ls kb/modules/` confirms both, and both were then
  read in full. This is exactly the failure the `dismech-terms` skill documents at
  step 3a - an unverified justification that tells the next reviewer to skip the
  one check that would catch it - landing on module selection rather than on a
  term binding.

  What was declared, after reading both modules:

  - `dermal_epidermal_junction_adhesion_failure` on the two skin-arm nodes. CD151
    belongs in that module's trigger class: it is a component of the extracellular
    attachment network, not an intracellular filament protein, which is the scope
    boundary that module draws when it excludes KRT5 and KRT14.
  - `nephrotic_podocyte_injury` on the renal node. That module's chain is an
    inherited adhesion or cytoskeletal defect destabilizing the podocyte, giving
    foot-process effacement, barrier breakdown, proteinuria and glomerulosclerosis,
    and every step of it is separately evidenced here.

  Conforming to only one would have asserted that one organ arm is the disease,
  which is what the earlier draft got wrong in substance as well as in provenance.

  One caveat on the skin conformance, recorded in `discussions` rather than
  buried: the module's organising axis is the ultrastructural cleavage plane, and
  in this disease that plane is not settled. PMID:29138120 reports intraepidermal
  keratinocyte dysadhesion in the lower epidermis on electron microscopy, while
  PMID:35519797 reports subepidermal separation on biopsy. Conformance is declared
  at the attachment-defect and loss-of-adhesive-integrity nodes, which hold either
  way, and not at the module's dermal-epidermal separation node, which does not.

  No GeneReviews chapter exists for this disorder. Checked offline with
  `just check-genereviews kb/disorders/Epidermolysis_Bullosa_Simplex_7_With_Nephropathy_And_Deafness.yaml`
  against the committed Bookshelf index; it reports NO_CHAPTER for GeneReviews.
  The phenotype baseline is therefore the primary literature: five published
  probands from four families as of the reports cited here.

  Two claims that appear in the sources were deliberately NOT curated. The
  beta-thalassemia minor and the bilateral cervical ribs reported in the original
  Indian Jewish family (PMID:15265795, restated in PMID:38188895) are
  co-segregating findings in one consanguineous pedigree with no proposed
  mechanistic link to CD151, and are not asserted here as features of the
  syndrome. The "atypical cystic fibrosis" and epilepsy in PMID:35519797 are
  argued by its authors to be part of a unified CD151 process, but that argument
  rests on tissue-expression overlap rather than on any demonstrated mechanism;
  the phenotypes are recorded with that reasoning quoted and marked as a single
  unreplicated observation rather than folded into the pathograph.

  The OpenScientist deep-research report independently reached the same conclusion
  on the first of those: it attributes the beta-thalassemia minor to the proximity
  of CD151 at 11p15.5 to the beta-globin cluster in the index kindred rather than
  to any CD151-intrinsic effect. That is corroboration of an exclusion already
  made, not new content.

  `just preflight-dr` on that report returns a WARN reading "Report cites OMIM
  602243 but MONDO:0012190 xrefs OMIM 609057". This is a false positive and no
  identity problem, but not for the reason first recorded here. The report cites
  #609057 three times, at lines 560, 616 and 655, and every one is written
  `**OMIM:** #609057`. The extractor's pattern allows only whitespace between the
  `OMIM` token and the number, so the markdown bold defeats it and the phenotype MIM
  is never seen at all; the only identifier it can read is `OMIM 602243`, the CD151
  gene MIM, which happens to appear unbolded. Both numbers are correct for this
  disease. Tested directly against the pattern rather than inferred - reported as
  issue #12414, which measures 67 committed reports carrying a MIM that is invisible
  for the same reason.

  Two suggestions from review were considered and not taken, recorded here so they
  are not re-raised. Modelling the blood-pressure dependence as an `environmental:`
  entry with `influences_mechanisms` was declined on two grounds: intraglomerular
  filtration pressure is an intrinsic haemodynamic variable rather than an exposure,
  and ECTO has no term for it - `l~blood pressure` returns nothing, `l~hypertens`
  returns only drug-exposure classes (`ECTO:2000001`, `ECTO:9001744`), and
  `l~pressure` returns only ambient air and water pressure classes. The fact is
  carried structurally instead, as evidence on the GBM node, as the
  `target_mechanisms` link on RAAS blockade, and as the modifier knowledge gap. A
  hearing *treatment* was likewise not asserted: no CD151 report describes a device,
  a fitting or an audiological outcome in any proband, so what the literature
  supports is the referral and the surveillance, and that is curated under
  `diagnosis` with the workup sentence that names it.

  Six phenotypes are deliberately left with no causal in-link: nail dystrophy,
  poikiloderma, alopecia, premature loss of permanent teeth, enamel hypoplasia and
  esophageal stricture. They are all reported, and all recorded with their own
  evidence, but no source proposes a mechanism for any of them. Wiring them to the
  keratinocyte dysadhesion node would assert that the same intraepidermal adhesion
  failure produces hair, tooth, nail and oesophageal disease, which is a plausible
  guess and not a published claim - and for the enamel and tooth findings it is not
  even obviously right, since ameloblast and hair-follicle biology are not where the
  cleavage plane in this disease sits. They are left as an open curation question
  rather than closed with an invented edge. The renal and cutaneous arms are wired,
  which took phenotype connectivity here from 4/13 to 7/13.
references:
- reference: PMID:15265795
  title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
  tags: []
  findings:
  - statement: >-
      The founding report. Three MER2-negative patients of Indian Jewish origin,
      homozygous for a single-nucleotide insertion in CD151 exon 5 truncating the
      protein before its integrin-binding domain, with end-stage kidney disease,
      sensorineural deafness and pretibial epidermolysis bullosa.
- reference: PMID:29138120
  title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
  tags: []
  findings:
  - statement: >-
      An independent consanguineous family with a homozygous CD151 donor splice-site
      allele deleting exon 5, complete absence of CD151 protein on the proband's
      skin, and keratinocyte dysadhesion in the lower epidermis on electron
      microscopy. Establishes CD151 as an epidermolysis bullosa gene.
- reference: PMID:35278129
  title: "Basement membrane defects in CD151-associated glomerular disease."
  tags: []
  findings:
  - statement: >-
      A homozygous truncating CD151 variant in a child with nephrotic-range
      proteinuria, with thickened glomerular basement membrane and podocyte
      effacement on biopsy, and a zebrafish CRISPR knockdown in which proteinuria
      was rescued by wild-type but not by variant CD151 mRNA.
- reference: PMID:35519797
  title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
  tags: []
  findings:
  - statement: >-
      The fifth recorded CD151 proband, homozygous for the nonsense allele
      p.Gln136*, presenting with focal segmental glomerulosclerosis, sensorineural
      hearing loss, pretibial bullae and dental and nail changes, and misdiagnosed
      and immunosuppressed for years as bullous pemphigoid before genetic testing.
- reference: PMID:38188895
  title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
  tags: []
  findings:
  - statement: >-
      A Saudi proband homozygous for p.Arg165* whose proteinuria was an incidental
      finding, reported specifically to document how wide the phenotypic range is
      on a single CD151 genotype.
- reference: PMID:31488507
  title: "Tetraspanin CD151 and integrin α3β1 contribute to the stabilization of integrin α6β4-containing cell-matrix adhesions."
  tags: []
  findings:
  - statement: >-
      Keratinocyte cell-biology showing that CD151 acts through integrin alpha-3/beta-1
      to stabilise a hybrid alpha-6/beta-4 adhesion structure, and that true
      keratin-anchored hemidesmosomes form and persist without CD151 - which is why
      the skin split in this disease is intraepidermal rather than junctional.
- reference: PMID:28615054
  title: "End-stage kidney disease in patient with epidermolysis bullosa - what are the treatment options? - case report."
  tags: []
  findings:
  - statement: >-
      Not a CD151 case, and carried deliberately. A woman with laminin-5
      epidermolysis bullosa, bilateral sensorineural deafness and oesophageal
      stenosis who reached end-stage renal disease, in whom kidney transplantation
      was pursued once dialysis access proved difficult. The authors conclude that
      no renal replacement modality should be ruled out in epidermolysis bullosa.
      It is the nearest thing to a transplant outcome in this disease group, and it
      sits on the other side of the same adhesion - laminin is the ligand whose
      binding CD151 stabilises.
- reference: PMID:17015618
  title: "Kidney failure in mice lacking the tetraspanin CD151."
  tags: []
  findings:
  - statement: >-
      The report that generated the Cd151-null mouse. It reproduces the human renal
      pathology with age - massive proteinuria, focal glomerulosclerosis, GBM
      disorganization and tubular cystic dilation - and states in the same sentence
      that neither skin integrity nor hearing is impaired. That explicit double
      negative is the reason the cochlear and cutaneous arms of this disease have no
      model support.
- reference: PMID:22201679
  title: "Blood pressure influences end-stage renal disease of Cd151 knockout mice."
  tags: []
  findings:
  - statement: >-
      Two things this entry depends on. Podocyte-specific deletion alone causes
      glomerular nephropathy, placing the renal lesion at the podocyte; and the
      global null on a resistant background only develops nephropathy once
      filtration pressure is raised, which is the evidence behind the
      mechanical-load premise. ACE inhibition prolonged median life span on the
      susceptible background.
- reference: PMID:32667818
  title: "An update on the RAPH blood group system."
  tags: []
  findings:
  - statement: >-
      The blood-group side of the same protein. CD151 carries the sole antigen
      (MER2) of RAPH, ISBT system 25, and RAPH-null is associated with this disease.
      It also gives the full laminin-binding integrin partner set including alpha-7/beta-1,
      which is wider than the set of organs the disease affects.
- reference: PMID:22338088
  title: "Morphology and migration of podocytes are affected by CD151 levels."
  tags: []
  findings:
  - statement: >-
      Podocyte cell-line work showing that CD151 knockdown reduces beta-1 integrin
      expression and podocyte cell area, giving a cellular mechanism for the
      adhesion failure seen in the patient glomerulus.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic CD151 loss-of-function alleles. Every published proband is homozygous,
    and all but one arose in a consanguineous or founder pedigree; no compound
    heterozygote has been reported. Carriers are usually asymptomatic, but the
    recessive label should not be read as strictly all-or-nothing: in the Saudi
    pedigree two heterozygous sisters had partial phenotypes - one steroid-responsive
    nephrotic syndrome, the other hearing impairment with low-grade proteinuria -
    while other heterozygous relatives were unaffected. That is one family and is
    recorded in `discussions` rather than asserted as a general carrier phenotype.
  evidence:
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrotic syndrome (NS)-epidermolysis bullosa (EB) sensorineural deafness syndrome is an autosomal recessive rare genetic disease caused by a CD151 gene homozygous mutation on chromosome 11p15.5."
    explanation: "States the inheritance mode and the homozygous CD151 lesion that defines it."
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140."
    explanation: "The founding pedigree: three affected homozygotes, consistent with recessive inheritance."
pathophysiology:
- name: CD151 Loss of Function
  biological_scale: MOLECULAR
  role: Initiating genetic lesion
  description: >-
    Biallelic CD151 alleles that truncate the protein before or within its large
    extracellular loop. The reported lesions are a frameshifting single-nucleotide
    insertion stopping translation at codon 140, a donor splice-site change that
    removes the whole of exon 5, and the nonsense alleles p.Gln136* and p.Arg165*.
    What they have in common is loss of the integrin-binding region, so the
    resulting protein cannot perform the one function CD151 has in this disease.
  genetic_context:
    gene:
      preferred_term: CD151
      term:
        id: hgnc:1630
        label: CD151
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      All published alleles are truncating and homozygous. No missense or
      hypomorphic allele has been reported, so there is no allelic series here to
      grade severity against.
  genes:
  - preferred_term: CD151
    term:
      id: hgnc:1630
      label: CD151
  evidence:
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resultant truncated protein would lack its integrin-binding domain."
    explanation: "Names the specific functional consequence of the founding allele: loss of the region through which CD151 binds its integrin partners."
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence of proband's skin and Western blot of skin proteins with a monoclonal antibody revealed complete absence of CD151."
    explanation: "Demonstrates at protein level that the splice allele produces a null, not a reduced-function product."
  downstream:
  - target: Destabilization of Laminin-Binding Integrin Adhesion Complexes
    description: >-
      Without the integrin-binding region there is no lateral organiser to hold the
      laminin-binding integrins in their high-avidity state.
    evidence:
    - reference: PMID:15265795
      reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tetraspanin CD151 forms very stable laminin-binding complexes with integrins alpha3beta1 and alpha6beta1 in kidney and alpha3beta1 and alpha6beta4 in skin."
      explanation: "Identifies the complexes that the truncated protein can no longer form, in exactly the two tissues this disease affects."
- name: Destabilization of Laminin-Binding Integrin Adhesion Complexes
  biological_scale: MOLECULAR
  conforms_to: "dermal_epidermal_junction_adhesion_failure#Basement Membrane Zone Attachment Component Defect"
  role: Shared molecular lesion upstream of all three organ arms
  description: >-
    CD151 normally clusters integrin alpha-3/beta-1 and alpha-6/beta-4 laterally
    and stabilises their engagement with laminin in the underlying basement
    membrane. In its absence the receptors are still expressed but the adhesion
    they mediate is weaker and less persistent. This single molecular failure is
    what makes the disorder multi-organ: the same integrin-laminin axis anchors
    basal keratinocytes to laminin-332 in skin and podocytes to laminin-521 in the
    glomerulus.
  molecular_functions:
  - preferred_term: laminin binding by the CD151-integrin complex
    term:
      id: GO:0043236
      label: laminin binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: integrin-mediated cell-matrix adhesion
    term:
      id: GO:0033627
      label: cell adhesion mediated by integrin
    modifier: DECREASED
  evidence:
  - reference: PMID:31488507
    reference_title: "Tetraspanin CD151 and integrin α3β1 contribute to the stabilization of integrin α6β4-containing cell-matrix adhesions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "We show that CD151, through binding to integrin α3β1, plays a critical role in the stabilization of an adhesion structure with a distinct molecular composition of hemidesmosomes with tetraspanin features."
    explanation: "Direct cell-biological demonstration that CD151 works by stabilising a laminin-binding integrin adhesion, which is the lesion this node asserts."
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "CD151 interacts with the laminin–integrin–actin axis, specifically via integrin α3β1, increasing the strength of integrin-dependent adhesion of the podocyte to laminin-521 in the GBM."
    explanation: "States the same mechanism on the renal side, naming the specific laminin isoform the podocyte binds."
  - reference: PMID:32667818
    reference_title: "An update on the RAPH blood group system."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "CD151 regulates interactions with laminin-binding integrins α3β1, α6β1, α6β4, and α7β1 and is expressed on red blood cells as well as many other tissues and cancer types."
    explanation: >-
      Gives the full laminin-binding partner set, which is wider than the two
      partners this node names and wider than the three organs the disease
      affects. That mismatch is the tissue-selectivity question recorded in the
      discussions, not an omission here.
  downstream:
  - target: Keratinocyte Dysadhesion in the Lower Epidermis
    description: Loss of the stabilised adhesion in basal and immediately suprabasal keratinocytes.
    evidence:
    - reference: PMID:29138120
      reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis."
      explanation: "Locates the adhesion failure in the patient's own skin, at the level this edge asserts."
  - target: Glomerular Basement Membrane Disorganization
    description: >-
      Loss of podocyte-GBM adhesion under the mechanical load of filtration, with
      secondary structural change in the membrane itself.
    evidence:
    - reference: PMID:15265795
      reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We conclude that CD151 is essential for the proper assembly of the glomerular and tubular basement membrane in kidney, has functional significance in the skin, is probably a component of the inner ear, and could play a role in erythropoiesis."
      explanation: "The founding paper's own conclusion that the renal basement membrane is a direct target of CD151 loss."
  - target: Cochlear Basement Membrane Involvement
    description: >-
      The inner-ear arm. Note the founding paper states this as an inference from
      the clinical phenotype rather than from direct cochlear study.
    evidence:
    - reference: PMID:15265795
      reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "is probably a component of the inner ear"
      explanation: "The authors' own hedged inference. Graded INDIRECT because the claim is reasoned back from the deafness in their patients, not from cochlear tissue."
- name: Keratinocyte Dysadhesion in the Lower Epidermis
  biological_scale: CELLULAR
  conforms_to: "dermal_epidermal_junction_adhesion_failure#Loss of Adhesive Integrity at a Defined Cleavage Plane"
  role: Cutaneous arm
  description: >-
    Basal and lower-epidermal keratinocytes separate from one another and from the
    matrix under minor mechanical stress. The split is intraepidermal, which is what
    classifies this as an epidermolysis bullosa simplex rather than a junctional
    form, and it sits alongside intact keratin-anchored hemidesmosomes - cell-biology
    work shows those form and persist without CD151.
  cell_types:
  - preferred_term: basal keratinocyte of the epidermis
    term:
      id: CL:0002187
      label: basal cell of epidermis
  biological_processes:
  - preferred_term: keratinocyte cell-matrix adhesion
    term:
      id: GO:0007160
      label: cell-matrix adhesion
    modifier: DECREASED
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy showed intracellular disruption and cell-cell dysadhesion of keratinocytes in the lower epidermis."
    explanation: "Ultrastructural evidence from patient skin for the cellular lesion this node names."
  - reference: PMID:31488507
    reference_title: "Tetraspanin CD151 and integrin α3β1 contribute to the stabilization of integrin α6β4-containing cell-matrix adhesions."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "In contrast, hemidesmosomes, keratin filament-associated adhesions that contain integrin α6β4, plectin, BP180 (encoded by COL17A1) and BP230 (encoded by DST), do not require CD151 for their formation or maintenance."
    explanation: "Explains why the cleavage plane is intraepidermal rather than at the hemidesmosome: CD151 is not needed to build a hemidesmosome."
  downstream:
  - target: Pretibial blistering
    description: The clinical blistering that follows loss of keratinocyte adhesion.
    evidence:
    - reference: PMID:15265795
      reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor."
      explanation: "Records the pretibial distribution of the blistering in the founding pedigree."
- name: Glomerular Basement Membrane Disorganization
  biological_scale: TISSUE
  conforms_to: "nephrotic_podocyte_injury#Podocyte Injury"
  role: Renal arm
  description: >-
    Podocyte attachment to the glomerular basement membrane is under continuous
    mechanical load during filtration, so a weakened integrin-laminin bond has
    structural consequences here that it does not have in quieter tissues. Patient
    biopsies show a thickened, disorganised GBM with podocyte foot-process
    effacement - the classical substrate of a glomerular protein leak.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: glomerular basement membrane
    term:
      id: UBERON:0005777
      label: glomerular basement membrane
  biological_processes:
  - preferred_term: basement membrane organization
    term:
      id: GO:0071711
      label: basement membrane organization
    modifier: DECREASED
  evidence:
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
    explanation: "Direct ultrastructural observation in a CD151 patient of the tissue lesion this node asserts."
  - reference: PMID:22338088
    reference_title: "Morphology and migration of podocytes are affected by CD151 levels."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "CD151 knockdown in podocytes reduced β(1)-integrin expression and podocyte cell area, indicating diminished adherence and/or spreading."
    explanation: "Gives the cellular mechanism behind the tissue lesion. INDIRECT because it is a knockdown in a mouse podocyte line, not the patient's glomerulus."
  - reference: PMID:22201679
    reference_title: "Blood pressure influences end-stage renal disease of Cd151 knockout mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Although global Cd151-null B6 mice were not susceptible to renal disease, as has been shown previously, increasing blood and transcapillary filtration pressure induced nephropathy in these mice."
    explanation: >-
      Evidence for the mechanical-load premise this node rests on: the same null
      allele is silent in the kidney until filtration pressure is raised, so it is
      the load across the adhesion rather than the loss of CD151 alone that
      produces the lesion. INDIRECT because it is a mouse experiment standing in
      for the human glomerulus.
  downstream:
  - target: Nephrotic range proteinuria
    description: Filtration-barrier failure following podocyte detachment and GBM disorganization.
    evidence:
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome."
      explanation: "Links the CD151 lesion to nephrotic-range protein loss in a patient."
  - target: Thickened glomerular basement membrane
    description: >-
      The membrane lesion itself as it appears on electron microscopy. This is the
      node's own structural readout rather than a downstream consequence of it, and
      is wired so the ultrastructural findings sit in the graph rather than beside it.
    evidence:
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
      explanation: "Direct ultrastructural observation of the membrane thickening in a CD151 patient."
  - target: Podocyte foot process effacement
    description: >-
      The podocyte-side readout of the same failed attachment, seen on the same
      biopsies. Effacement follows loss of the integrin-laminin anchorage that holds
      the foot processes against the membrane.
    evidence:
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
      explanation: "The same electron-microscopy observation, curated here for the foot-process finding."
  - target: Focal segmental glomerulosclerosis
    description: The sclerosing response that follows sustained podocyte loss.
    evidence:
    - reference: PMID:35519797
      reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "chronic kidney disease secondary to nephrotic syndrome from focal segmental glomerular sclerosis"
      explanation: "Records FSGS as the renal histology in a CD151 proband."
- name: Cochlear Basement Membrane Involvement
  biological_scale: TISSUE
  role: Auditory arm
  description: >-
    The least directly evidenced arm of the disease. Sensorineural hearing loss is
    consistent across probands, and CD151 is inferred to be a component of the
    inner ear, but no human or model cochlear tissue study has been reported, and
    the Cd151 knockout mouse does not reproduce the deafness. This node is curated
    because the phenotype is consistent and needs somewhere to attach, not because
    the mechanism is established.
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "is probably a component of the inner ear"
    explanation: "The only mechanistic statement in the literature about the auditory arm, and the authors hedge it."
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: REFUTE
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "The extrarenal features, including sensorineural deafness and bullous skin lesions, have not been replicated in knockout mouse models"
    explanation: "Records that the mouse null does not reproduce the deafness, which refutes any claim that the auditory arm is a settled, model-supported mechanism. REVIEW_SYNTHESIS because this review is summarising the model literature rather than reporting its own knockout."
  downstream:
  - target: Sensorineural hearing impairment
    description: The clinical auditory phenotype.
    evidence:
    - reference: PMID:15265795
      reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor."
      explanation: "Reports sensorineural deafness in the founding pedigree."
phenotypes:
- name: Pretibial blistering
  category: Clinical
  description: >-
    Trauma-induced bullae with a characteristic distribution over the shins and
    distal extensor surfaces. The pretibial localisation is consistent enough
    across probands to be part of the condition's descriptive name.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Pretibial blistering
    term:
      id: HP:0012221
      label: Pretibial blistering
  evidence:
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor."
    explanation: "Pretibial blistering in the founding pedigree."
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she demonstrated linear pretibial and upper extremity extensor bullae on minimally erythematous bases"
    explanation: "The examination finding in an independently ascertained proband, with the same pretibial and extensor distribution."
- name: Nephrotic range proteinuria
  category: Clinical
  description: >-
    Glomerular protein loss, in the reported patients ranging from an incidental
    dipstick finding to overt nephrotic syndrome. It is the feature most likely to
    be detected first, and the one that brings the diagnosis into reach.
  diagnostic: true
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nephrotic range proteinuria
    term:
      id: HP:0012593
      label: Nephrotic range proteinuria
  evidence:
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria."
    explanation: "Nephrotic-range proteinuria in a genetically confirmed CD151 patient."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this report, we discuss a rare case related to a Saudi patient with genetic syndrome who presented with NS and EB."
    explanation: "An independent proband presenting with nephrotic syndrome alongside the skin disease."
- name: Focal segmental glomerulosclerosis
  category: Pathological
  description: >-
    The glomerular histology reported in CD151 probands who come to biopsy after
    sustained proteinuria.
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic kidney disease secondary to nephrotic syndrome from focal segmental glomerular sclerosis"
    explanation: "Names FSGS as this proband's renal histology."
  sequelae:
  - target: Stage 5 chronic kidney disease
    description: >-
      The sclerosis is the lesion the renal course runs through: once enough
      glomeruli are lost the filtration reserve goes with them. Not universal -
      one later proband's renal disease was an incidental dipstick finding - so
      this is the reported trajectory rather than an obligate one.
    evidence:
    - reference: PMID:35519797
      reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "chronic kidney disease secondary to nephrotic syndrome from focal segmental glomerular sclerosis"
      explanation: >-
        Chains the histology to the renal outcome in one proband. INDIRECT because
        the sentence says chronic kidney disease rather than stage 5 specifically;
        the end-stage endpoint is carried by the founding pedigree's own evidence on
        the target phenotype.
- name: Podocyte foot process effacement
  category: Pathological
  description: >-
    Ultrastructural loss of the interdigitating foot-process architecture on
    electron microscopy of patient glomeruli, the morphological readout of failed
    podocyte adhesion.
  phenotype_term:
    preferred_term: Podocyte foot process effacement
    term:
      id: HP:0031266
      label: Podocyte foot process effacement
  evidence:
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
    explanation: "Direct electron-microscopy observation of foot-process effacement in a CD151 patient."
- name: Thickened glomerular basement membrane
  category: Pathological
  description: >-
    Structural thickening of the GBM on electron microscopy, distinguishing this
    from the thinning seen in some other hereditary nephropathies.
  phenotype_term:
    preferred_term: Thickened glomerular basement membrane
    term:
      id: HP:0004722
      label: Thickened glomerular basement membrane
  evidence:
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement."
    explanation: "The same observation, curated here for the membrane finding specifically."
- name: Stage 5 chronic kidney disease
  category: Clinical
  description: >-
    Progression to kidney failure. Reached by all three probands in the founding
    pedigree, but explicitly not the universal course - one later proband's renal
    disease was an incidental dipstick finding.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We examined CD151 in 3 MER2-negative patients (2 are sibs) of Indian Jewish origin with end-stage kidney disease."
    explanation: "End-stage kidney disease in all three founding probands."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This syndrome is reported to have an adolescent age of onset and is characterized by hereditary nephritis, leading to NS and ESRD, associated with sensorineural hearing loss and pretibial skin blistering [Table 1].[2]"
    quote_role: BACKGROUND
    explanation: "Restates progression to end-stage renal disease as part of the established clinical description. Marked BACKGROUND because this case report is summarising prior reports here, not its own result."
- name: Sensorineural hearing impairment
  category: Clinical
  description: >-
    Sensorineural deafness, present across the reported probands. The mechanism is
    the least evidenced part of the disease and is not reproduced in the mouse null.
  diagnostic: true
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor."
    explanation: "Sensorineural deafness in the founding pedigree."
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also has a history of sensorineural hearing loss and is followed by a gastrointestinal specialist for dysphagia with small esophageal strictures."
    explanation: "Independent confirmation in a separately ascertained proband."
- name: Nail dystrophy
  category: Clinical
  description: Onychodystrophy, reported in most probands and sometimes the presenting complaint.
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
    explanation: "Nail dystrophy in the examination of the Iranian proband."
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria."
    explanation: "Nail dystrophy as a presenting feature in an independent proband."
- name: Poikiloderma
  category: Clinical
  description: >-
    Mottled pigmentation with atrophy and telangiectasia. It is this feature, with
    the blistering, that led to an initial misdiagnosis of Kindler syndrome in one
    proband.
  phenotype_term:
    preferred_term: Poikiloderma
    term:
      id: HP:0001029
      label: Poikiloderma
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination of the 33-year old proband, initially diagnosed as Kindler syndrome, revealed widespread blistering, particularly on pretibial areas, poikiloderma"
    explanation: "Poikiloderma on examination, and the reason the Kindler misdiagnosis was made."
- name: Alopecia
  category: Clinical
  description: Early-onset hair loss, patchy in the reported probands.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
    explanation: "Early-onset alopecia in the Iranian proband."
- name: Premature loss of permanent teeth
  category: Clinical
  description: Dental loss, with enamel hypoplasia reported separately in another proband.
  phenotype_term:
    preferred_term: Premature loss of permanent teeth
    term:
      id: HP:0006357
      label: Premature loss of permanent teeth
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
    explanation: "Loss of teeth in the Iranian proband."
- name: Enamel hypoplasia
  category: Clinical
  description: Deficient enamel formation, reported on examination in the fifth proband.
  phenotype_term:
    preferred_term: Enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onychodystrophy and dental enamel hypoplasia as well as scattered poikiloderma and patchy alopecia were also diagnosed."
    explanation: "Enamel hypoplasia on examination of the fifth reported proband."
- name: Esophageal stricture
  category: Clinical
  description: >-
    Oesophageal webbing and strictures with dysphagia, reported in two probands -
    the mucosal counterpart of the cutaneous fragility.
  phenotype_term:
    preferred_term: Esophageal stricture
    term:
      id: HP:0002043
      label: Esophageal stricture
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed widespread blistering, particularly on pretibial areas, poikiloderma, nail dystrophy, loss of teeth, early onset alopecia, and esophageal webbing and strictures"
    explanation: "Oesophageal webbing and strictures in the Iranian proband."
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also has a history of sensorineural hearing loss and is followed by a gastrointestinal specialist for dysphagia with small esophageal strictures."
    explanation: "Independent report of oesophageal strictures with dysphagia."
genetic:
- name: CD151
  gene_term:
    preferred_term: CD151
    term:
      id: hgnc:1630
      label: CD151
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: Biallelic truncating alleles (frameshift, nonsense, and a donor splice-site allele deleting exon 5)
  presence: Positive
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    CD151 is at 11p15.5 and also carries the MER2 antigen of the Raph blood group,
    so CD151-null individuals type MER2-negative. That is how the founding family
    was ascertained - through a blood-group discrepancy, not through the skin or
    kidney disease - and it remains a usable confirmatory test. No constraint
    metrics were consulted for this entry and none is claimed.
  evidence:
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140."
    explanation: "Establishes CD151 as the causative gene and gives the founding truncating allele."
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one family, a homozygous donor splice site mutation in CD151 (NM_139029; c.351+2T>C) at the exon 5/intron 5 border was identified, and RT-PCR and whole transcriptome analysis by RNA-seq confirmed deletion of the entire exon 5 encoding 25 amino acids."
    explanation: "An independent allele class - a splice-site change causing exon skipping - confirming the gene in a second family."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole genome sequencing results indicated a homozygous pathogenic variant identified in the CD151 gene (c.493C>T p.(Arg165*), which was consistent with a genetic diagnosis of autosomal recessive nephropathy with pretibial EB and deafness syndrome."
    explanation: "A third independent family and a third truncating allele."
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    The diagnosis is molecular. In practice it has been reached by an
    epidermolysis-bullosa gene panel, by targeted next-generation sequencing from a
    nephrology direction, and by whole genome sequencing - which route depends
    entirely on which specialty the patient reaches first. That is the core
    diagnostic problem in this disease: dermatology, nephrology and audiology each
    see a plausible isolated condition.
  diagnosis_term:
    preferred_term: next-generation sequencing gene panel
    term:
      id: NCIT:C101293
      label: Next Generation Sequencing
  evidence:
  - reference: PMID:29138120
    reference_title: "Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have developed a next-generation sequencing (NGS) panel targeting genes known to be mutated in skin fragility disorders, including tetraspanin CD151 expressed in keratinocytes at the dermal-epidermal junction."
    explanation: "The skin-fragility panel route to the diagnosis."
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria."
    explanation: "States the diagnostic gap from the nephrology side, which is why proteinuric patients are missed."
- name: MER2 Blood Group Phenotyping
  description: >-
    CD151 carries the MER2 antigen, so loss of CD151 makes red cells MER2-negative.
    Absent immunoreactivity to anti-CD151/MER2 on patient erythrocytes has been used
    as a confirmatory assay, and MER2-negativity is what identified the founding
    family in the first place. It is a cheap orthogonal check on a novel variant.
  diagnosis_term:
    preferred_term: MER2/CD151 erythrocyte antigen phenotyping
    term:
      id: NCIT:C210738
      label: Blood Typing Test
  evidence:
  - reference: PMID:35278129
    reference_title: "Basement membrane defects in CD151-associated glomerular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells."
    explanation: "Records the MER2 red-cell assay being used as a confirmatory test in a patient."
  - reference: PMID:15265795
    reference_title: "CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that CD151 expresses the MER2 blood group antigen and is located on erythrocytes."
    explanation: "Establishes the biological basis of the blood-group test."
  - reference: PMID:32667818
    reference_title: "An update on the RAPH blood group system."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lack of the RAPH protein is associated with nephropathy with pretibial epidermolysis bullosa and deafness."
    explanation: "The blood-group literature's own statement of the association, placing MER2-negativity as a marker for this disease rather than an incidental type."
- name: Audiological Assessment and Surveillance
  description: >-
    The hearing loss is sensorineural, bilateral and part of the defining triad, so
    audiology is one of the three specialties a CD151 patient needs referred to
    alongside nephrology and haematology. The literature supports the referral and
    the surveillance; it does not describe a device, a fitting or an outcome in any
    reported proband, which is why no hearing treatment is asserted in this entry.
  diagnosis_term:
    preferred_term: diagnostic audiology testing
    term:
      id: NCIT:C217379
      label: Diagnostic Audiology Testing
  evidence:
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the case of CD151 defects, urinalysis, renal ultrasound, and complete blood count should be considered, as well as referrals to nephrology, hematology, and audiology specialists."
    explanation: "A CD151-specific workup recommendation that names audiology referral explicitly."
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence or incidence estimate exists. The literature is a
    small number of case reports: PMID:35519797 describes its patient as "the fifth
    recorded case of EBS with nephropathy in relation to CD151 defects", and
    PMID:38188895 and PMID:35278129 add further probands after that. The count is
    recorded as a literature count rather than converted into a rate, because no
    denominator is available.
  evidence:
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the fifth recorded case of EBS with nephropathy in relation to CD151 defects and, to our knowledge, the first case to be reported with neurologic and chloride transport complications."
    explanation: "The only published count of reported cases, and the basis for the ULTRA_RARE band."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrotic syndrome (NS)-epidermolysis bullosa (EB) sensorineural deafness syndrome is an autosomal recessive rare genetic disease caused by a CD151 gene homozygous mutation on chromosome 11p15.5."
    explanation: "Characterises the condition as rare; supports the band without supplying a rate."
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    The renal arm dominates prognosis and is what makes the burden variable rather
    than uniformly high. All three probands in the founding pedigree reached
    end-stage kidney disease and two were on peritoneal dialysis; the Saudi proband
    reported eighteen years later had proteinuria detected incidentally at home and
    was managed on an oral ACE inhibitor. The skin disease is a lifelong dressing
    and wound-care burden but is not by itself life-limiting. Nothing in the cited
    sources characterises survival for the condition as a whole, so no mortality
    claim is made.
  evidence:
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Both siblings had hereditary nephritis, pre-tibial EB, and beta-thalassemia minor with nephrotic range proteinuria and ESRD and were on peritoneal dialysis."
    explanation: "The severe end of the range - dialysis-dependent renal failure. Marked BACKGROUND because this case report is summarising the earlier pedigree, not its own patient."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings emphasize that even a single genotype can result in variable phenotypic expression, necessitating the assessment of the pleiotropic effects of the disease on the patient, which can range from severe to mild."
    explanation: "The authors' own statement that severity ranges from severe to mild, which is what VARIABLE encodes."
treatments:
- name: Renin-Angiotensin System Blockade
  description: >-
    An oral ACE inhibitor is the reported pharmacological management of the
    proteinuria. In the one patient followed longitudinally, proteinuria resolved
    and then relapsed in step with adherence to lisinopril, which is about as close
    to a within-patient control as this literature offers. The proposed mechanism -
    lowering intraglomerular pressure and so the mechanical load on an
    adhesion-compromised capillary wall - fits the pathophysiology directly, and is
    supported in the Cd151-null mouse.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lisinopril
      term:
        id: CHEBI:43755
        label: lisinopril
  target_mechanisms:
  - target: Glomerular Basement Membrane Disorganization
    description: >-
      Reduces intraglomerular pressure, lowering the mechanical demand on a
      podocyte-GBM attachment that CD151 loss has already weakened.
    evidence:
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "This was alleviated with angiotensin-converting enzyme inhibitors, which may act by reducing the mechanical load on the capillary wall by decreasing intraglomerular pressure [9, 10]."
      explanation: "Gives the proposed mechanism and the mouse result behind it. INDIRECT and MODEL_ORGANISM because the observation is in Cd151-knockout mice, and the mechanism is offered as a possibility by the authors."
  evidence:
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had relapses of proteinuria that are most likely explained by poor compliance with Lisinopril."
    explanation: "Proteinuria tracking adherence in a CD151 patient is the strongest human evidence available that the drug is doing something here."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was kept on PO Lisinopril with follow-up visits."
    explanation: "Records the specific agent and route used in long-term management."
- name: Wound Care and Withdrawal of Immunosuppression
  description: >-
    Skin management is non-adherent dressings, protection and nutrition. The
    substantive therapeutic finding in this disease is a negative one: because the
    blistering is often mistaken for an acquired autoimmune blistering disease,
    patients are treated with immunosuppressants that cannot work on a structural
    adhesion defect. One proband had years of topical and systemic corticosteroids,
    minocycline, nicotinamide, mycophenolate mofetil and methotrexate with no
    benefit, and improved substantially once they were all withdrawn in favour of
    skin care. Stopping the wrong treatment is the actionable consequence of making
    the genetic diagnosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: wound care management
    term:
      id: NCIT:C116681
      label: Wound Care Management
  target_mechanisms:
  - target: Keratinocyte Dysadhesion in the Lower Epidermis
    description: >-
      Protective and mechanical, not mechanistic: dressings reduce the shear that
      separates keratinocytes, they do not restore the adhesion complex.
    evidence:
    - reference: PMID:35519797
      reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The blisters substantially improved with this regimen, and she was referred to a multidisciplinary EB clinic for further evaluation and treatment."
      explanation: "Records improvement on skin care after immunosuppression was withdrawn. INDIRECT for the mechanism: an uncontrolled single-patient observation with two simultaneous changes."
  evidence:
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was tapered off of all forms of immunosuppressants, with a care plan that was shifted to careful skin care, nutrition, and ocular health."
    explanation: "The management change itself: immunosuppression withdrawn, supportive skin care substituted."
  - reference: PMID:35519797
    reference_title: "Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had trialed topical corticosteroids, minocycline, nicotinamide, mycophenolate mofetil, methotrexate, and protracted courses of systemic corticosteroids with negligible therapeutic benefit prior to this visit."
    explanation: "Documents the failed immunosuppressive regimens, which is what makes withdrawal the right move rather than merely a neutral one."
- name: Renal Replacement Therapy
  description: >-
    Dialysis for those who reach end-stage kidney disease. Peritoneal dialysis is
    what is recorded for the founding siblings. No transplant outcome has been
    reported in a CD151 patient - `CD151 AND kidney transplantation` returns
    nothing in PubMed, and `epidermolysis bullosa nephropathy deafness transplant`
    returns only PMID:28615054, which is a different gene. So nothing is asserted
    here about whether the disease recurs in a graft, which, given that the lesion
    is in the recipient's podocytes and not circulating, would be worth knowing.

    The nearest evidence is that case report, and it is worth carrying because the
    gene it names sits on the other side of the same adhesion: a woman with
    laminin-5 epidermolysis bullosa, bilateral sensorineural deafness and
    oesophageal stenosis who reached end-stage renal disease, in whom
    transplantation was pursued after dialysis access proved difficult. Its authors
    conclude that no modality should be ruled out in epidermolysis bullosa. That is
    a statement about EB as a group rather than about CD151, and it is recorded as
    such.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: peritoneal dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  evidence:
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Both siblings had hereditary nephritis, pre-tibial EB, and beta-thalassemia minor with nephrotic range proteinuria and ESRD and were on peritoneal dialysis."
    explanation: "The only record of renal replacement therapy in this disorder. Marked BACKGROUND: the citing case report is restating the earlier pedigree's course, not reporting its own."
  - reference: PMID:28615054
    reference_title: "End-stage kidney disease in patient with epidermolysis bullosa - what are the treatment options? - case report."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "There should be no limitations in renal replacement therapy in patients with epidermolysis bullosa."
    explanation: >-
      The nearest available statement on renal replacement therapy in this disease
      group. INDIRECT because the reported patient has laminin-5 epidermolysis
      bullosa rather than a CD151 defect - the conclusion is about epidermolysis
      bullosa as a group, and is carried here as context, not as a CD151 finding.
  - reference: PMID:28615054
    reference_title: "End-stage kidney disease in patient with epidermolysis bullosa - what are the treatment options? - case report."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "There have been few reports concerning ESRD in this specific group of patients in the available literature."
    explanation: "Records how thin the evidence base is for renal replacement therapy across epidermolysis bullosa at all, which is why the CD151-specific negative is unsurprising rather than suspicious."
animal_models:
- name: Cd151-null mouse
  species: Mouse
  genotype: Cd151 global knockout
  publication: PMID:17015618
  description: >-
    The mammalian null. Its behaviour is strain-dependent in a way that matters for
    interpretation: on the FVB background it develops early massive proteinuria with
    focal segmental glomerulosclerosis and kidney failure, while on C57BL/6 there is
    no spontaneous kidney phenotype at all and proteinuria appears only with
    hypertension. Neither background reproduces the deafness or the skin blistering.
  modeled_mechanisms:
  - target: Glomerular Basement Membrane Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces the renal arm on a permissive background, including the FSGS
      endpoint seen in patients.
    limitations: >-
      The phenotype depends on strain background rather than on the lesion, so the
      model reports genetic modifiers as much as it reports CD151. It also covers
      only one of the three affected organs.
    evidence:
    - reference: PMID:17015618
      reference_title: "Kidney failure in mice lacking the tetraspanin CD151."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation."
      explanation: "The report that generated this model, stating the renal phenotype it reproduces."
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "Global deletion of CD151 in mouse models on the FVB background exhibits early, massive proteinuria with associated focal segmental glomerulosclerosis (FSGS) and subsequent kidney failure [7, 8]."
      explanation: "Later synthesis naming the strain on which the phenotype is penetrant, which the originating report does not."
  - target: Cochlear Basement Membrane Involvement
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The mouse null is deliberately recorded as a negative for the extrarenal arms.
      This is the structural reason the auditory mechanism in this disease is
      unresolved rather than merely uninvestigated.
    limitations: >-
      Neither the sensorineural deafness nor the bullous skin disease appears in the
      knockout on any reported background, so the model cannot be used to study
      either arm, and the human inner-ear claim has no model support.
    evidence:
    - reference: PMID:17015618
      reference_title: "Kidney failure in mice lacking the tetraspanin CD151."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice."
      explanation: "The originating report's own explicit negative for both extrarenal arms, stated in the same sentence as the renal positive."
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: "The extrarenal features, including sensorineural deafness and bullous skin lesions, have not been replicated in knockout mouse models [7]."
      explanation: "Confirms the negative has held across models since, not just in the originating report."
- name: Podocyte-specific Cd151 conditional knockout mouse
  species: Mouse
  genotype: Podocyte-restricted conditional Cd151 deletion
  publication: PMID:22201679
  description: >-
    The cell-autonomy test. Deleting Cd151 only in podocytes is sufficient to
    produce glomerular nephropathy, which is what licenses this entry to place the
    renal lesion at the podocyte rather than at the endothelium or the mesangium.
    The same study is also where the mechanical-load gate comes from: the global
    null on a resistant background stays well until filtration pressure is raised,
    and ACE inhibition on a susceptible background extends life span.
  modeled_mechanisms:
  - target: Glomerular Basement Membrane Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Podocyte-restricted deletion reproduces the glomerular lesion, isolating the
      podocyte as the cell in which the CD151 requirement is non-redundant.
    limitations: >-
      Covers the renal arm only, and a conditional allele cannot speak to whether
      the skin and cochlear arms are likewise cell-autonomous.
    evidence:
    - reference: PMID:22201679
      reference_title: "Blood pressure influences end-stage renal disease of Cd151 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Moreover, in vivo podocyte-specific deletion of Cd151 led to glomerular nephropathy."
      explanation: "Establishes that loss of CD151 in the podocyte alone is sufficient for the renal phenotype."
    readouts:
    - name: Median life span under ACE inhibition
      target: Glomerular Basement Membrane Disorganization
      direction: RESTORED
      interpretation: >-
        Pharmacological reduction of filtration pressure partially rescues the
        outcome, which is the model-side counterpart of the RAAS-blockade
        management this entry records as standard of care.
      evidence:
      - reference: PMID:22201679
        reference_title: "Blood pressure influences end-stage renal disease of Cd151 knockout mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: "Importantly, blocking the angiotensin-converting enzyme in renal disease-susceptible global Cd151-null FVB mice prolonged their median life span."
        explanation: "The measured rescue arm behind the nephroprotection rationale."
- name: cd151 CRISPR-depleted zebrafish
  species: Zebrafish
  genotype: CRISPR-Cas9 cd151 depletion, with wild-type and variant CD151 mRNA rescue arms
  publication: PMID:35278129
  description: >-
    The functional assay that upgraded a novel human truncating variant from
    uncertain to disease-causing. Depletion produces proteinuria; wild-type human
    CD151 mRNA rescues it and mRNA carrying the patient variant does not, which is
    an allele-specific test rather than a general knockdown phenotype.
  modeled_mechanisms:
  - target: Nephrotic range proteinuria
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces the proteinuric phenotype and, through the differential rescue,
      attributes it specifically to loss of CD151 function.
    limitations: >-
      Zebrafish pronephric glomerular architecture differs from the mammalian
      kidney, and the assay reads out proteinuria alone - it says nothing about the
      skin or ear arms. The rescue is by injected mRNA, so it tests the variant
      protein's function rather than the endogenous locus.
    readouts:
    - name: Proteinuria after cd151 depletion, with mRNA rescue
      target: Nephrotic range proteinuria
      direction: RESTORED
      interpretation: >-
        Wild-type CD151 mRNA restores the filtration barrier; the variant transcript
        does not, which is what makes this an allele-specific functional result.
      evidence:
      - reference: PMID:35278129
        reference_title: "Basement membrane defects in CD151-associated glomerular disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence."
        explanation: "The measurement and its direction, including the negative variant arm that gives the result its specificity."
    evidence:
    - reference: PMID:35278129
      reference_title: "Basement membrane defects in CD151-associated glomerular disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9."
      explanation: "States the purpose the model was built for: establishing that this specific variant is disease-causing."
discussions:
- discussion_id: cd151_cochlear_mechanism_unmodelled
  status: OPEN
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Cochlear Basement Membrane Involvement
  prompt: >-
    Sensorineural hearing loss is consistent across CD151 probands, but the mouse
    null does not become deaf and no cochlear tissue from a patient or a model has
    been examined. Is the human deafness a direct consequence of CD151 loss in the
    inner ear, and if so which structure fails?
  rationale: >-
    The only mechanistic statement in the literature is the founding paper's hedge
    that CD151 "is probably a component of the inner ear", reasoned backwards from
    the patients' deafness. The one model that could test it is explicitly reported
    as not reproducing the phenotype. So the auditory arm of this disease rests on
    clinical co-occurrence alone, and a reader should not take its presence in the
    pathograph as evidence that the mechanism is known. This is the case
    HUMAN_MODEL_MISMATCH exists for rather than a plain KNOWLEDGE_GAP: evidence in
    the model system exists and is negative.
- discussion_id: cd151_heterozygote_partial_phenotype
  status: OPEN
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#CD151
  - inheritance#Autosomal recessive
  prompt: >-
    Do heterozygous CD151 carriers have a partial phenotype? Two heterozygous
    sisters in one pedigree had steroid-responsive nephrotic syndrome and hearing
    impairment with low-grade proteinuria, while other heterozygous relatives in the
    same family were asymptomatic.
  rationale: >-
    A single consanguineous family cannot distinguish a genuine carrier phenotype
    from coincidence or from a second segregating variant, and no carrier series has
    been published. It matters practically, because if carriers do have low-grade
    proteinuria then the relatives identified during cascade testing need renal
    follow-up rather than reassurance. The observation is recorded here rather than
    curated as a phenotype so that it is not read as an established feature.
- discussion_id: cd151_epilepsy_and_chloride_transport
  status: OPEN
  kind: KNOWLEDGE_GAP
  attaches_to:
  - disease#Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness
  prompt: >-
    Are the epilepsy and the sweat-chloride-positive "atypical cystic fibrosis"
    phenotype reported in one CD151 proband part of the syndrome?
  rationale: >-
    The authors argue they are, on the grounds that CD151 is expressed in the
    nervous system and in bronchial epithelium where CFTR operates, and that an
    extensive workup found no alternative cause. That argument is from tissue
    expression, not from any demonstrated mechanism, and it rests on one patient.
    Until a second proband is reported with either feature it cannot be
    distinguished from comorbidity in a consanguineous pedigree, so neither is
    curated as a phenotype of this disorder.
- discussion_id: cd151_cleavage_plane_unsettled
  status: OPEN
  kind: CONTROVERSY
  attaches_to:
  - pathophysiology#Keratinocyte Dysadhesion in the Lower Epidermis
  prompt: >-
    Where does the skin split in CD151 disease - intraepidermally, or below the
    epidermis? The two ultrastructural reports disagree.
  rationale: >-
    This matters more than an ultrastructural detail normally would, because the
    cleavage plane is what classifies an epidermolysis bullosa subtype, and it is
    the organising axis of the `dermal_epidermal_junction_adhesion_failure` module
    this entry conforms to.

    PMID:29138120 examined the proband's skin by transmission electron microscopy
    and reports intracellular disruption and cell-cell dysadhesion of keratinocytes
    in the lower epidermis - an intraepidermal plane, which is what classifies the
    disease as an EB simplex. PMID:35519797 reports biopsies showing subepidermal
    separation in its patient, though it notes that neither immunofluorescence
    mapping nor transmission electron microscopy was available there, so the two
    observations are not of equal technical weight.

    Cell biology favours the intraepidermal reading: PMID:31488507 shows that
    keratin-anchored hemidesmosomes form and persist without CD151, so the
    hemidesmosomal plane should not be the one that fails. But that is an argument
    from a cell line, not a second patient biopsy.

    Consequence for this entry: conformance to the module is declared at the
    attachment-defect and loss-of-adhesive-integrity nodes, which hold on either
    reading, and deliberately not at its dermal-epidermal separation node. Settling
    it needs immunofluorescence mapping or electron microscopy on a further
    proband.
- discussion_id: cd151_renal_severity_modifiers_unknown
  status: OPEN
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Glomerular Basement Membrane Disorganization
  - phenotypes#Stage 5 chronic kidney disease
  prompt: >-
    What determines whether a CD151-null individual reaches end-stage kidney disease
    in adolescence or carries an incidental proteinuria into adulthood?
  rationale: >-
    The renal course is the most variable thing about this disease and nothing
    explains the variance. All three probands in the founding pedigree reached
    end-stage kidney disease; a later proband's renal involvement was an incidental
    dipstick finding, on a comparably truncating allele. Allele severity therefore
    does not obviously predict outcome.

    The mouse says the missing factor is at least partly extrinsic to CD151. The same
    null allele produces early massive proteinuria and kidney failure on an FVB
    background and essentially no spontaneous kidney phenotype on C57BL/6, and the
    resistant background becomes susceptible once blood and transcapillary filtration
    pressure are raised. So there is a genetic modifier acting somewhere, and a
    haemodynamic gate on top of it, and in humans neither has been identified.

    This is a knowledge gap rather than a controversy: nobody has proposed competing
    answers, because the cohort needed to look for one does not exist. It is recorded
    because it bears directly on management - if filtration pressure is the gate, the
    case for early and sustained RAAS blockade in an asymptomatic CD151 patient is
    stronger than the single reported human drug response can establish on its own.
  evidence:
  - reference: PMID:22201679
    reference_title: "Blood pressure influences end-stage renal disease of Cd151 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Although global Cd151-null B6 mice were not susceptible to renal disease, as has been shown previously, increasing blood and transcapillary filtration pressure induced nephropathy in these mice."
    explanation: "Establishes both halves of the gap: a strain-dependent modifier, and filtration pressure as a gate on the same lesion."
  - reference: PMID:38188895
    reference_title: "Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 13-year-old boy was brought by his mother to the emergency room in February 2019 with a history of incidental finding of proteinuria 6 months earlier, when the mother had tested his urine using a urine dipstick test at home."
    explanation: "The human end of the same variance: a CD151 proband whose renal disease was asymptomatic and found incidentally, against a founding pedigree that all reached end-stage disease."
📚

References & Deep Research

References

11
PMID:15265795
CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin.
1 finding
The founding report. Three MER2-negative patients of Indian Jewish origin, homozygous for a single-nucleotide insertion in CD151 exon 5 truncating the protein before its integrin-binding domain, with end-stage kidney disease, sensorineural deafness and pretibial epidermolysis bullosa.
PMID:29138120
Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy.
1 finding
An independent consanguineous family with a homozygous CD151 donor splice-site allele deleting exon 5, complete absence of CD151 protein on the proband's skin, and keratinocyte dysadhesion in the lower epidermis on electron microscopy. Establishes CD151 as an epidermolysis bullosa gene.
PMID:35278129
Basement membrane defects in CD151-associated glomerular disease.
1 finding
A homozygous truncating CD151 variant in a child with nephrotic-range proteinuria, with thickened glomerular basement membrane and podocyte effacement on biopsy, and a zebrafish CRISPR knockdown in which proteinuria was rescued by wild-type but not by variant CD151 mRNA.
PMID:35519797
Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature.
1 finding
The fifth recorded CD151 proband, homozygous for the nonsense allele p.Gln136*, presenting with focal segmental glomerulosclerosis, sensorineural hearing loss, pretibial bullae and dental and nail changes, and misdiagnosed and immunosuppressed for years as bullous pemphigoid before genetic testing.
PMID:38188895
Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report.
1 finding
A Saudi proband homozygous for p.Arg165* whose proteinuria was an incidental finding, reported specifically to document how wide the phenotypic range is on a single CD151 genotype.
PMID:31488507
Tetraspanin CD151 and integrin α3β1 contribute to the stabilization of integrin α6β4-containing cell-matrix adhesions.
1 finding
Keratinocyte cell-biology showing that CD151 acts through integrin alpha-3/beta-1 to stabilise a hybrid alpha-6/beta-4 adhesion structure, and that true keratin-anchored hemidesmosomes form and persist without CD151 - which is why the skin split in this disease is intraepidermal rather than junctional.
PMID:28615054
End-stage kidney disease in patient with epidermolysis bullosa - what are the treatment options? - case report.
1 finding
Not a CD151 case, and carried deliberately. A woman with laminin-5 epidermolysis bullosa, bilateral sensorineural deafness and oesophageal stenosis who reached end-stage renal disease, in whom kidney transplantation was pursued once dialysis access proved difficult. The authors conclude that no renal replacement modality should be ruled out in epidermolysis bullosa. It is the nearest thing to a transplant outcome in this disease group, and it sits on the other side of the same adhesion - laminin is the ligand whose binding CD151 stabilises.
PMID:17015618
Kidney failure in mice lacking the tetraspanin CD151.
1 finding
The report that generated the Cd151-null mouse. It reproduces the human renal pathology with age - massive proteinuria, focal glomerulosclerosis, GBM disorganization and tubular cystic dilation - and states in the same sentence that neither skin integrity nor hearing is impaired. That explicit double negative is the reason the cochlear and cutaneous arms of this disease have no model support.
PMID:22201679
Blood pressure influences end-stage renal disease of Cd151 knockout mice.
1 finding
Two things this entry depends on. Podocyte-specific deletion alone causes glomerular nephropathy, placing the renal lesion at the podocyte; and the global null on a resistant background only develops nephropathy once filtration pressure is raised, which is the evidence behind the mechanical-load premise. ACE inhibition prolonged median life span on the susceptible background.
PMID:32667818
An update on the RAPH blood group system.
1 finding
The blood-group side of the same protein. CD151 carries the sole antigen (MER2) of RAPH, ISBT system 25, and RAPH-null is associated with this disease. It also gives the full laminin-binding integrin partner set including alpha-7/beta-1, which is wider than the set of organs the disease affects.
PMID:22338088
Morphology and migration of podocytes are affected by CD151 levels.
1 finding
Podocyte cell-line work showing that CD151 knockdown reduces beta-1 integrin expression and podocyte cell area, giving a cellular mechanism for the adhesion failure seen in the patient glomerulus.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Entry scope. This entry curates the CD151-related syndrome as a single DISEASE. The stub recorded no MONDO descendants, and MONDO carries one causal gene relation for MONDO:0012190, to hgnc:1630 CD151 (read from stubs/Epidermolysis_Bullosa_Simplex_7_With_Nephropathy_And_Deafness.yaml, which `just enrich-stubs` wrote from MONDO). All published probands carry biallelic CD151 alleles and share the skin/kidney/inner-ear triad, so there is one conserved pathograph here and no case for a GROUPING. No `has_subtypes` rows are declared: the reported allele classes are all truncating (frameshift, nonsense and a whole-exon-skipping splice allele) and the phenotypic differences between probands do not track allele class, so a subtype split would assert a structure the literature does not support. Severity is genuinely uncoupled from genotype here and that is worth stating rather than smoothing over. PMID:38188895 reports a proband homozygous for p.Arg165* whose renal disease was detected incidentally on a home dipstick, and makes the point explicitly that one genotype gives variable expression; PMID:15265795 reports end-stage kidney disease in all three of its probands. Both are recorded, and no severity ordering is asserted between them. Module conformance: two modules, one per organ arm, plus a correction. An earlier draft of this note claimed a module search had been run and had found only `podocyte_injury_and_glomerular_filtration_barrier_failure` and `epithelial_barrier_dysfunction`. That was false in a way worth recording: no module of the first name exists in `kb/modules/` at all, and the real candidates were missed. The automated second-opinion comment on the claim issue (dismech#12389) named `dermal_epidermal_junction_adhesion_failure` and `nephrotic_podocyte_injury`; `ls kb/modules/` confirms both, and both were then read in full. This is exactly the failure the `dismech-terms` skill documents at step 3a - an unverified justification that tells the next reviewer to skip the one check that would catch it - landing on module selection rather than on a term binding. What was declared, after reading both modules: - `dermal_epidermal_junction_adhesion_failure` on the two skin-arm nodes. CD151 belongs in that module's trigger class: it is a component of the extracellular attachment network, not an intracellular filament protein, which is the scope boundary that module draws when it excludes KRT5 and KRT14. - `nephrotic_podocyte_injury` on the renal node. That module's chain is an inherited adhesion or cytoskeletal defect destabilizing the podocyte, giving foot-process effacement, barrier breakdown, proteinuria and glomerulosclerosis, and every step of it is separately evidenced here. Conforming to only one would have asserted that one organ arm is the disease, which is what the earlier draft got wrong in substance as well as in provenance. One caveat on the skin conformance, recorded in `discussions` rather than buried: the module's organising axis is the ultrastructural cleavage plane, and in this disease that plane is not settled. PMID:29138120 reports intraepidermal keratinocyte dysadhesion in the lower epidermis on electron microscopy, while PMID:35519797 reports subepidermal separation on biopsy. Conformance is declared at the attachment-defect and loss-of-adhesive-integrity nodes, which hold either way, and not at the module's dermal-epidermal separation node, which does not. No GeneReviews chapter exists for this disorder. Checked offline with `just check-genereviews kb/disorders/Epidermolysis_Bullosa_Simplex_7_With_Nephropathy_And_Deafness.yaml` against the committed Bookshelf index; it reports NO_CHAPTER for GeneReviews. The phenotype baseline is therefore the primary literature: five published probands from four families as of the reports cited here. Two claims that appear in the sources were deliberately NOT curated. The beta-thalassemia minor and the bilateral cervical ribs reported in the original Indian Jewish family (PMID:15265795, restated in PMID:38188895) are co-segregating findings in one consanguineous pedigree with no proposed mechanistic link to CD151, and are not asserted here as features of the syndrome. The "atypical cystic fibrosis" and epilepsy in PMID:35519797 are argued by its authors to be part of a unified CD151 process, but that argument rests on tissue-expression overlap rather than on any demonstrated mechanism; the phenotypes are recorded with that reasoning quoted and marked as a single unreplicated observation rather than folded into the pathograph. The OpenScientist deep-research report independently reached the same conclusion on the first of those: it attributes the beta-thalassemia minor to the proximity of CD151 at 11p15.5 to the beta-globin cluster in the index kindred rather than to any CD151-intrinsic effect. That is corroboration of an exclusion already made, not new content. `just preflight-dr` on that report returns a WARN reading "Report cites OMIM 602243 but MONDO:0012190 xrefs OMIM 609057". This is a false positive and no identity problem, but not for the reason first recorded here. The report cites #609057 three times, at lines 560, 616 and 655, and every one is written `**OMIM:** #609057`. The extractor's pattern allows only whitespace between the `OMIM` token and the number, so the markdown bold defeats it and the phenotype MIM is never seen at all; the only identifier it can read is `OMIM 602243`, the CD151 gene MIM, which happens to appear unbolded. Both numbers are correct for this disease. Tested directly against the pattern rather than inferred - reported as issue #12414, which measures 67 committed reports carrying a MIM that is invisible for the same reason. Two suggestions from review were considered and not taken, recorded here so they are not re-raised. Modelling the blood-pressure dependence as an `environmental:` entry with `influences_mechanisms` was declined on two grounds: intraglomerular filtration pressure is an intrinsic haemodynamic variable rather than an exposure, and ECTO has no term for it - `l~blood pressure` returns nothing, `l~hypertens` returns only drug-exposure classes (`ECTO:2000001`, `ECTO:9001744`), and `l~pressure` returns only ambient air and water pressure classes. The fact is carried structurally instead, as evidence on the GBM node, as the `target_mechanisms` link on RAAS blockade, and as the modifier knowledge gap. A hearing *treatment* was likewise not asserted: no CD151 report describes a device, a fitting or an audiological outcome in any proband, so what the literature supports is the referral and the surveillance, and that is curated under `diagnosis` with the workup sentence that names it. Six phenotypes are deliberately left with no causal in-link: nail dystrophy, poikiloderma, alopecia, premature loss of permanent teeth, enamel hypoplasia and esophageal stricture. They are all reported, and all recorded with their own evidence, but no source proposes a mechanism for any of them. Wiring them to the keratinocyte dysadhesion node would assert that the same intraepidermal adhesion failure produces hair, tooth, nail and oesophageal disease, which is a plausible guess and not a published claim - and for the enamel and tooth findings it is not even obviously right, since ameloblast and hair-follicle biology are not where the cleavage plane in this disease sits. They are left as an open curation question rather than closed with an invented edge. The renal and cutaneous arms are wired, which took phenotype connectivity here from 4/13 to 7/13.

Reconcile OpenScientist deep-research report · 2026-09-21T06:12:11Z · View source

Reconciled the OpenScientist deep-research run against the committed entry. Substantive changes. The Cd151-null mouse model was citing a 2022 review for both its positive and its negative claim; both are now sourced to PMID:17015618, the 2006 report that generated the mice, which states the renal phenotype and the skin/hearing negative in the same sentence. The review is kept alongside with quote_role REVIEW_SYNTHESIS where it adds something the primary source does not (the FVB strain dependence, and that the negative has held since). Added a podocyte-specific Cd151 conditional knockout as a separate animal model (PMID:22201679). It makes a different claim from the global null - that loss of CD151 in the podocyte alone is sufficient - which is what licenses this entry to place the renal lesion at the podocyte and to conform that node to nephrotic_podocyte_injury. It carries a RESTORED readout for the ACE-inhibition life-span arm. The Glomerular Basement Membrane Disorganization node asserted in prose that podocyte attachment is under continuous mechanical load and that this is why the adhesion defect bites in the kidney and not in quieter tissues. That claim had no evidence behind it. PMID:22201679 supplies it: the same null allele is silent on a resistant background until filtration pressure is raised. Added the RAPH blood group review (PMID:32667818) in two places - the full laminin-binding integrin partner set including alpha-7/beta-1, which is wider than the three organs the disease affects and so sharpens rather than answers the tissue-selectivity question; and the blood-group literature's own statement of the disease association on the MER2 phenotyping definition. Two report findings recorded as notes rather than content. The report independently attributes the beta-thalassemia minor to 11p15.5 proximity to the beta-globin cluster rather than to CD151, corroborating an exclusion this entry had already made. And just preflight-dr returns a WARN on OMIM identity that is a false positive: the report carries phenotype MIM 609057 and gene MIM 602243 on one line and the check does not distinguish them. Term discipline. Two CURIEs offered by the report were not taken. UBERON:0002966 is obsolete. HP:0011904, offered for beta-thalassemia minor, is Persistence of hemoglobin F - an unrelated concept - and the phenotype is excluded from this entry in any case. Six of the report's term-validation label mismatches were inspected and are table-column artifacts (the validator read the frequency column) rather than wrong-concept bindings. Validation: just validate passes, 68/68 snippets verified against cached references (was 61/61). check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-coarse-phenotypes, check-delivery-system and check-case-collisions all clean. check-genereviews re-confirms NO_CHAPTER offline against the committed Bookshelf index, which is the negative the notes record.

Create: Epidermolysis Bullosa Simplex 7 With Nephropathy And Deafness (CD151) · 2026-09-21T05:24:23Z · View source

New DISEASE entry for MONDO:0012190, the CD151 tetraspanin disorder. Why one entry for three organs. CD151 is not a structural component of the basement membrane; it is a lateral organiser that holds the laminin-binding integrins alpha-3/beta-1 and alpha-6/beta-4 in a high-avidity association with their laminin ligands. Losing it weakens the same class of cell-matrix adhesion wherever an epithelium is anchored that way, which is why one gene gives skin fragility, a progressive glomerular disease and sensorineural hearing loss. The pathograph is built around that shared molecular lesion with three organ arms branching from it, rather than as three parallel chains. Module conformance, and a correction to an earlier draft of the entry's notes. The first draft claimed a module search had been run and had found only 'podocyte_injury_and_glomerular_filtration_barrier_failure' and 'epithelial_barrier_dysfunction'. That was false: no module of the first name exists in kb/modules/ at all. The automated second-opinion comment on claim issue #12389 named dermal_epidermal_junction_adhesion_failure and nephrotic_podocyte_injury; ls kb/modules/ confirms both, and both were then read in full and declared - the first on the two skin-arm nodes, the second on the renal node. This is the exact failure the dismech-terms skill documents at step 3a, an unverified justification that tells the next reviewer to skip the check that would catch it, landing on module selection rather than on a term binding. Recorded rather than silently fixed. One caveat on the skin conformance, carried as a CONTROVERSY discussion: the module's organising axis is the ultrastructural cleavage plane, and in this disease that plane is not settled. PMID:29138120 reports intraepidermal keratinocyte dysadhesion on electron microscopy; PMID:35519797 reports subepidermal separation on biopsy, though without immunofluorescence mapping or TEM. Conformance is declared at the attachment-defect and loss-of-adhesive-integrity nodes, which hold either way, and not at the module's dermal-epidermal separation node, which does not. The same second-opinion comment independently caught a fabricated CURIE in the claim issue body: I had written hgnc:1885 for CD151, which is actually CGA. The stub had hgnc:1630 correct on the line I was paraphrasing. The issue body was corrected with the error left visible rather than edited away. Curation choices. The auditory arm is curated with its evidence deliberately weak and marked so: the only mechanistic statement in the literature is the founding paper's hedge that CD151 'is probably a component of the inner ear', reasoned backwards from the deafness, and PMID:35278129 states the Cd151 knockout mouse does not reproduce the deafness - curated as a REFUTE item and as a HUMAN_MODEL_MISMATCH discussion. Heterozygous relatives in the Saudi pedigree had partial phenotypes (steroid-responsive nephrotic syndrome; hearing impairment with low-grade proteinuria) while others were asymptomatic; that is one family and is carried as a KNOWLEDGE_GAP rather than asserted as a carrier phenotype. The strongest treatment evidence is a within-patient one - proteinuria resolving and relapsing in step with lisinopril adherence - and the most actionable finding is negative: one proband had years of failed immunosuppression for a presumed autoimmune blistering disease and improved once it was withdrawn. Two claims in the sources were deliberately not curated: the beta-thalassemia minor and cervical ribs in the founding consanguineous pedigree (co-segregating, no proposed link to CD151), and the epilepsy and sweat-chloride-positive 'atypical cystic fibrosis' in PMID:35519797, whose authors argue for inclusion from tissue-expression overlap rather than from any demonstrated mechanism. Deep research: an OpenScientist run for this entry was launched at the same time as the others in this batch and had not completed when the entry was committed. It will be reconciled and committed in a follow-up round before the pull request is opened, and this record will be followed by a second one covering that round. Validation. just validate passes with 61/61 snippets verified. just validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-coarse-phenotypes and check-qualifier-terms all pass. just check-genereviews reports NO_CHAPTER for both collections against the committed Bookshelf index snapshot of 2026-09-10.

OpenScientist ▸
Key Findings
openscientist-autonomous 17 citations 2026-09-21T06:02:01.224044

Key Findings

Finding 1 — CD151 loss-of-function is the cause of the disease

The causal genetic lesion was established by Karamatic Crew et al. (2004, Blood), who examined three MER2-negative patients of Indian Jewish origin (two siblings) presenting with end-stage kidney disease. All three were homozygous for a single-nucleotide insertion, insG383, in exon 5 of CD151 on chromosome 11p15.5. In the words of the authors: "The 3 patients are homozygous for a single nucleotide insertion (G383) in exon 5 of CD151, causing a frameshift and premature stop signal at codon 140. The resultant truncated protein would lack its integrin-binding domain" (PMID: 15265795). This is a frameshift/truncating loss-of-function mechanism: the protein is severely truncated (140 residues versus the full-length ~253-residue tetraspanin) and cannot engage its integrin partners.

The same report established the core clinical picture beyond kidney disease: "In addition to hereditary nephritis the sibs have sensorineural deafness, pretibial epidermolysis bullosa, and beta-thalassemia minor" (PMID: 15265795). This defines the recognizable triad — nephropathy + skin fragility + deafness — plus a hematologic feature (β-thalassemia minor, likely reflecting the 11p15.5 locus proximity to the β-globin cluster in the index kindred rather than a CD151-intrinsic effect).

Finding 2 — Cd151-null mice recapitulate the renal phenotype via podocyte–GBM adhesion failure

The renal mechanism was validated in animal models. Sachs et al. (2006) reported that Cd151-null mice "with age... develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice" (PMID: 17015618). This faithfully reproduces the human nephropathy — proteinuria, focal segmental glomerulosclerosis (FSGS), glomerular basement membrane (GBM) disorganization — while notably NOT reproducing the skin and ear phenotypes, an important model limitation (see Limitations).

Critically, the renal phenotype is modifier- and blood-pressure-dependent. Sachs et al. (2012) showed that CD151 strengthens α3β1-mediated podocyte adhesion to laminin, and that "blocking the angiotensin-converting enzyme in renal disease-susceptible global Cd151-null FVB mice prolonged their median life span" (PMID: 22201679). Disease onset depended on genetic strain background (FVB susceptible) and systemic blood pressure — directly implicating mechanical/hemodynamic stress as a disease amplifier and RAAS blockade as protective. Independently, Naylor et al. (2022) used CRISPR-Cas9 zebrafish to validate a novel human truncating CD151 variant as disease-causing, extending model evidence to a second organism (PMID: 35278129).

Finding 3 — Mechanism: CD151 scaffolds laminin-binding integrin adhesion complexes governing basement-membrane integrity

CD151 (HGNC:1630; NCBI Gene 977; UniProt P48509; locus 11p15.5) is a tetraspanin that forms "very stable laminin-binding complexes with integrins alpha3beta1 and alpha6beta1 in kidney and alpha3beta1 and alpha6beta4 in skin" (PMID: 15265795). This single sentence unifies the kidney and skin phenotypes at a molecular level: the same tetraspanin organizes different but overlapping integrin sets in each tissue.

In keratinocytes, CD151 (via α3β1) stabilizes α6β4-containing hemidesmosomes and "hybrid" cell-matrix adhesions (PMID: 31488507). In podocytes, CD151 strengthens α3β1–laminin adhesion (PMID: 22201679). More broadly, tetraspanins are plasma-membrane organizers that concentrate partner integrins into tetraspanin-enriched microdomains; their perturbation has organ-level consequences: "Perturbations of tetraspan-integrin assemblies can have dramatic impacts on renal tissue morphogenesis, resulting in a disruption of normal glomerular architecture and selectivity" (PMID: 17565278). This provides the direct causal bridge from CD151 loss to impaired glomerular filtration selectivity (proteinuria).

Finding 4 — Expanded phenotypic spectrum: nephrotic syndrome, epilepsy, and MER2/RAPH-null blood type

The phenotype has expanded beyond the original triad in later reports. Dunn et al. (2022) described syndromic EBS with nephropathy AND epilepsy from a CD151 tetraspanin defect, explicitly "expanding the spectrum" (PMID: 35519797). Almokali et al. (2024) described nephrotic-syndrome–epidermolysis-bullosa–sensorineural-deafness syndrome, an autosomal recessive rare disease presenting with pretibial EB (PMID: 38188895). And the blood-group connection was clarified by Keller (2020): CD151 carries the MER2 antigen of the RAPH blood group system (ISBT 25), and "Lack of the RAPH protein is associated with nephropathy with pretibial epidermolysis bullosa and deafness" (PMID: 32667818). This same review documented the full integrin partner set: "CD151 regulates interactions with laminin-binding integrins α3β1, α6β1, α6β4, and α7β1 and is expressed on red blood cells as well as many other tissues and cancer types" (PMID: 32667818) — notably adding α7β1 (relevant to muscle/vascular basement membranes) to the list.

Finding 5 — Prognosis and treatment: progressive ESRD requiring renal replacement; supportive/nephroprotective care

The renal course is relentlessly progressive to ESRD (the index patients presented with end-stage disease). No curative therapy exists. Mouse data support RAAS blockade as nephroprotective — ACE inhibition "prolonged their median life span" in disease-susceptible Cd151-null FVB mice (PMID: 22201679). Sasaki (2022) frames CD151-deficient nephropathy as a "mechanosensitive nephropathy" whose onset depends on genetic background/modifier genes, mechanistically analogous to Alport syndrome and TNS2-deficient nephropathy (PMID: 35444113). For patients who reach ESRD, renal replacement therapy is feasible despite EB-related access challenges: "There should be no limitations in renal replacement therapy in patients with epidermolysis bullosa" (PMID: 28615054).

Finding 6 — Epidemiology, inheritance, and diagnostic approach

This is an ultra-rare autosomal recessive disorder with fewer than ~20 molecularly confirmed patients reported worldwide; prevalence is not estimable (<1/1,000,000) and no incidence data exist. Expected sex ratio is ~1:1 (M:F). The index kindred was Indian Jewish (two siblings), consistent with a founder/consanguineous origin: "We examined CD151 in 3 MER2-negative patients (2 are sibs) of Indian Jewish origin with end-stage kidney disease" (PMID: 15265795); additional cases have arisen in other consanguineous backgrounds (PMID: 38188895). Penetrance is high in humans but strongly background-dependent in mice. Because "CD151 is not routinely screened for in patients with nephrotic-range proteinuria" (PMID: 35278129), broad NGS (whole-exome/whole-genome sequencing) is the recommended path to diagnosis. Key differentials include Alport syndrome, LAMB2/Pierson syndrome, and ITGA3-related interstitial lung disease-nephrotic syndrome-epidermolysis bullosa (ILNEB) (PMID: 24220332).

Detailed Report by Disease-Characteristic Domain

1. Disease Information

CD151-deficiency syndrome is a hereditary, multisystem basement-membrane disorder. The disease name "Epidermolysis Bullosa Simplex 7 with Nephropathy and Deafness" reflects historical classification within the EB simplex spectrum (skin blistering) combined with the two other cardinal organ features.

Key identifiers: - MONDO: MONDO:0012190 - OMIM: #609057 (Nephropathy with pretibial epidermolysis bullosa and deafness); gene CD151 602243 - HGNC: HGNC:1630 | NCBI Gene: 977 | UniProt: P48509 | Ensembl: ENSG00000177697 - Orphanet: listed under CD151-related / EB with nephropathy and deafness - ICD-10: Q81.- (epidermolysis bullosa) with N-codes for nephropathy; ICD-11: EC30.- (epidermolysis bullosa simplex)

Synonyms / alternative names: Nephropathy with pretibial epidermolysis bullosa and deafness; CD151 deficiency; Epidermolysis bullosa, pretibial, with nephropathy and deafness; RAPH-null (MER2-negative) associated syndrome; NS-EB-sensorineural deafness syndrome.

Source of information: Characterized almost entirely from individual patient reports (aggregated case reports/case series), not population-level EHR datasets, owing to extreme rarity.

2. Etiology

Causal factor: Purely genetic — biallelic loss-of-function variants in CD151. No environmental or infectious cause. The prototypic variant is c.383dupG (insG383) in exon 5, producing a frameshift → stop at codon 140 and loss of the integrin-binding domain (PMID: 15265795).

Genetic risk factors: The disease is Mendelian (biallelic CD151 LOF is causal). Modifier genes and genetic background strongly influence renal severity — demonstrated by strain-dependence in mice (FVB susceptible) (PMID: 22201679, PMID: 35444113). Consanguinity raises risk because the disorder is recessive and enriched in founder populations.

Environmental / lifestyle risk factors: No environmental cause, but mechanical stress and hypertension act as disease amplifiers — blood pressure influences the renal course (PMID: 22201679), and cutaneous blistering is provoked by mechanical friction/trauma (hallmark of EB simplex).

Protective factors: No genetic protective alleles established. Inferred protective measures: avoidance of skin trauma/friction, blood-pressure control, and RAAS blockade.

Gene–environment interactions: Best-documented is genotype (CD151-null) × hemodynamic load (blood pressure) gating renal disease onset and progression (PMID: 22201679), reframed as "mechanosensitive nephropathy" gated by modifier genes (PMID: 35444113).

3. Phenotypes

Phenotype Type Onset Severity/Course Frequency HPO suggestion
Hereditary nephropathy / proteinuria → ESRD Lab + clinical sign Childhood–young adult Progressive, severe Core (near-universal) HP:0000112; HP:0000093; HP:0003774
Nephrotic-range proteinuria / nephrotic syndrome Lab abnormality Childhood–young adult Progressive Frequent HP:0000100
FSGS / GBM disorganization Pathology finding Progressive Severe Core (biopsy) HP:0000097
Pretibial epidermolysis bullosa Physical manifestation Congenital/infancy Mechanically induced, chronic Core HP:0001075; HP:0008066
Nail dystrophy Physical manifestation Childhood Chronic Frequent HP:0008404
Bilateral sensorineural deafness Clinical sign Childhood Progressive/stable, bilateral Core HP:0000407
β-thalassemia minor Lab abnormality Congenital Mild Index kindred HP:0011904
Epilepsy Clinical sign Variable Variable Rare (expanded spectrum) HP:0001250
MER2/RAPH-null red cells Lab abnormality Congenital Asymptomatic marker Core —

Quality-of-life impact: Dominated by progressive renal failure (dialysis dependence, transplant needs), chronic painful skin blistering/wound care, and communication impairment from deafness — collectively imposing severe, lifelong disability. Formal EQ-5D/SF-36 data are unavailable for this ultra-rare disease.

4. Genetic / Molecular Information

  • Causal gene: CD151 (tetraspanin; HGNC:1630; OMIM 602243; locus 11p15.5).
  • Prototypic pathogenic variant: homozygous c.383dupG (insG383), exon 5, frameshift → premature stop at codon 140; type: frameshift/truncating; consequence: loss of function, deletion of integrin-binding domain (PMID: 15265795). Additional novel truncating variants have been functionally validated (PMID: 35278129).
  • Classification (ACMG/AMP): truncating LOF in a gene with established LOF mechanism → pathogenic/likely pathogenic.
  • Allele frequency: private/ultra-rare; not present at appreciable frequency in gnomAD.
  • Origin: germline, biallelic (autosomal recessive).
  • Modifier genes: unidentified in humans but demonstrably present (mouse strain-dependence; TNS2 modifier analogy) (PMID: 22201679, PMID: 35444113).
  • Epigenetic / chromosomal abnormalities: none reported.
  • Related gene (differential): ITGA3 (integrin α3) missense R628P causes an overlapping lung-kidney-skin disorder by disrupting α3 processing and CD151 binding (PMID: 24220332), underscoring the shared integrin–tetraspanin adhesion axis.

5. Environmental Information

No environmental, toxic, or infectious cause. Mechanical trauma provokes cutaneous blistering; hypertension/hemodynamic stress accelerates nephropathy (PMID: 22201679). No infectious agents are implicated. (Tetraspanins including CD151 participate in viral-entry biology in unrelated contexts, e.g. respiratory viruses [PMID: 36173052], but this has no bearing on disease causation here.)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic LOF mutation in CD151 (e.g., insG383 frameshift) leads to a truncated CD151 protein lacking its integrin-binding domain (PMID: 15265795).
  2. Loss of functional CD151 results in failure to scaffold laminin-binding integrins (α3β1, α6β1, α6β4, α7β1) into stable tetraspanin-enriched microdomains (PMID: 32667818, PMID: 15265795).
  3. Unscaffolded/redistributed integrins lead to weakened cell–laminin adhesion and reduced adhesive strength at the cell–basement-membrane interface (PMID: 22201679, PMID: 31488507).
  4. Weakened adhesion results in defective assembly and progressive disorganization of basement membranes across kidney, skin, and inner ear (PMID: 15265795, PMID: 17565278).
  5. Branch A — Kidney: GBM disorganization + podocyte foot-process effacement (under hemodynamic load) leads to loss of filtration selectivity → proteinuria → FSGS → progressive nephropathy → ESRD (PMID: 17015618, PMID: 17565278, PMID: 22201679).
  6. Branch B — Skin: destabilized α6β4 hemidesmosomes/α3β1 adhesions at the dermo-epidermal junction lead to mechanical fragility → pretibial epidermolysis bullosa + nail dystrophy (PMID: 31488507, PMID: 15265795).
  7. Branch C — Inner ear: basement-membrane defects in cochlear structures lead to (inferred) bilateral sensorineural deafness (PMID: 15265795; mechanism inferred, not directly demonstrated — mouse model does not reproduce deafness [PMID: 17015618]).
CD151 LOF mutation (insG383, exon 5 -> stop@140)
        |
     truncated CD151, no integrin-binding domain
        |
     failure to scaffold a3b1 / a6b1 / a6b4 / a7b1 in TEMs
        |
weakened integrin-laminin adhesion strength
        |
       basement-membrane assembly/maintenance failure
  +-------------+--------------+
      KIDNEY           SKIN         INNER EAR
   GBM disorg. +    DEJ fragility   BM defects
   podocyte FPE     (hemidesmo-     (cochlea)
|           some loss)          |
   proteinuria ->        |         sensorineural
   FSGS -> ESRD     pretibial EB     deafness
   [hemodynamic     + nail          (inferred)
    stress gates]   dystrophy
  • Molecular pathways / processes (GO): cell-substrate adhesion (GO:0031589); integrin-mediated signaling pathway (GO:0007229); basement membrane organization (GO:0071711); hemidesmosome assembly (GO:0031581); glomerular filtration (GO:0003094).
  • Protein dysfunction: loss of function / loss of scaffolding — truncated CD151 cannot bind integrins; downstream integrins are mislocalized and adhesion complexes destabilized.
  • Cell types involved (CL): podocyte (CL:0000653); keratinocyte (CL:0000312); glomerular endothelial cell (CL:1001005); cochlear hair cell / supporting cells.
  • Subcellular (GO CC): plasma-membrane tetraspanin-enriched microdomain; hemidesmosome (GO:0030056); basement membrane (GO:0005604).
  • Molecular profiling: CD151 appears as a hub gene in membranous-nephropathy transcriptomic analyses ([PMID: 37974210]), consistent with a role in glomerular biology, though associative rather than causal for this Mendelian disease.

7. Anatomical Structures Affected

  • Primary organs: kidney (glomerulus UBERON:0000074; glomerular basement membrane UBERON:0002966); skin (dermo-epidermal junction, esp. pretibial UBERON:0002097); inner ear/cochlea (UBERON:0001844).
  • Secondary/systemic: hematopoietic (β-thalassemia minor; red cells carry MER2/RAPH UBERON:0000178); nervous system (epilepsy in expanded spectrum).
  • Body systems: renal/urinary, integumentary, auditory/nervous, hematologic.
  • Tissue types: epithelial (podocytes, keratinocytes), specialized basement membrane (ECM/connective).
  • Cell populations (CL): podocytes (CL:0000653), keratinocytes (CL:0000312), cochlear hair cells.
  • Subcellular compartments: plasma-membrane microdomains, hemidesmosomes, basement membrane.
  • Localization/lateralization: nephropathy bilateral; deafness bilateral; skin blistering typically bilateral and pretibial (mechanically exposed lower legs).

8. Temporal Development

  • Onset: skin fragility often congenital/infancy; nephropathy and deafness typically manifest in childhood to young adulthood; pattern chronic/insidious.
  • Progression: renal disease is progressive (early proteinuria → FSGS → advanced CKD → ESRD); rate variable and modifier/blood-pressure dependent (PMID: 22201679, PMID: 35444113).
  • Course: chronic, lifelong; no spontaneous renal remission. Skin blistering chronic and mechanically episodic (flares with trauma).
  • Critical windows: early nephroprotection (blood-pressure/RAAS control) before advanced fibrosis is the key intervention window (inferred from mouse ACE-inhibition survival benefit).

9. Inheritance and Population

  • Inheritance: autosomal recessive; biallelic CD151 LOF.
  • Epidemiology: ultra-rare; <20 molecularly confirmed cases; prevalence <1/1,000,000 (not formally estimable); no incidence data.
  • Penetrance: high in humans with biallelic LOF; strongly background-dependent in mice.
  • Expressivity: variable (epilepsy, thalassemia, renal severity vary between cases).
  • Anticipation / mosaicism: not applicable / not reported.
  • Founder effect / consanguinity: index kindred Indian Jewish (2 sibs), consistent with founder/consanguineous origin (PMID: 15265795); other cases in consanguineous families (PMID: 38188895). North Indian carrier-screening data exist for other recessive disorders but not specifically CD151 ([PMID: 33138774]).
  • Carrier frequency: unknown/very low.
  • Sex ratio: ~1:1.

10. Diagnostics

  • Clinical/lab tests: urinalysis (proteinuria, nephrotic-range), serum creatinine/eGFR (declining), audiometry (bilateral sensorineural loss).
  • Renal biopsy (EM): thickened/disorganized/split GBM, podocyte foot-process effacement, FSGS (PMID: 17015618, PMID: 17565278).
  • Immunofluorescence / blood typing: reduced/absent CD151 in skin/kidney; MER2/RAPH-null red cells (PMID: 32667818).
  • Genetic testing: confirmatory biallelic CD151 sequencing via single-gene testing or, preferably, WES/WGS — because "CD151 is not routinely screened for in patients with nephrotic-range proteinuria" (PMID: 35278129), broad NGS captures otherwise-undiagnosed cases.
  • Differential diagnosis: Alport syndrome (COL4A3/4/5 — deafness + nephropathy, no EB), Pierson/LAMB2 syndrome, ITGA3-related ILNEB (PMID: 24220332), other EB subtypes.
  • Screening: carrier/cascade screening in affected families; prenatal testing feasible where the familial variant is known.

11. Outcome / Prognosis

  • Renal: progressive to ESRD requiring dialysis or transplantation; the dominant determinant of morbidity/mortality.
  • Life expectancy: reduced primarily by renal failure; renal replacement therapy is feasible and improves survival — "There should be no limitations in renal replacement therapy in patients with epidermolysis bullosa" (PMID: 28615054).
  • Morbidity: chronic skin wounds, hearing loss/communication impairment, dialysis dependence.
  • Prognostic factors: blood pressure, degree of proteinuria, rate of eGFR decline, and (in principle) modifier genotype (PMID: 22201679, PMID: 35444113).
  • QoL tools: no disease-specific validated instruments; general CKD/EB QoL measures apply.

12. Treatment

No curative or disease-specific therapy exists. Management is supportive and organ-directed.

Modality Intervention Evidence/Rationale NCIT suggestion
Nephroprotection ACE inhibitor / ARB (RAAS blockade), BP control ACE inhibition prolonged survival in Cd151-null FVB mice (PMID: 22201679) ACE inhibitor; Angiotensin receptor blocker
Renal replacement Hemodialysis, peritoneal dialysis, kidney transplant Feasible in EB patients (PMID: 28615054) Hemodialysis (NCIT:C15248); Kidney transplantation (NCIT:C15366)
Skin/wound care Non-adhesive dressings, trauma avoidance, infection control Standard EB management Wound care
Hearing Hearing aids, cochlear implantation, speech therapy Standard SNHL rehabilitation Hearing aid; Cochlear implant
Hematologic Monitoring of β-thalassemia minor (usually no treatment) Index kindred feature —
Neurologic Antiepileptic therapy if seizures Expanded spectrum (PMID: 35519797) Anticonvulsant
  • Pharmacogenomics: none specific.
  • Advanced therapeutics (gene/cell/RNA): none approved; conceptually plausible future gene-replacement targets given the monogenic LOF mechanism.
  • Experimental trials: no disease-specific NCT trials identified.

13. Prevention

  • Primary: genetic counseling for at-risk (consanguineous/founder) families; carrier screening and cascade testing; preimplantation/prenatal genetic diagnosis where the familial variant is known.
  • Secondary: early detection of proteinuria and hearing loss in known-carrier offspring; early nephroprotection.
  • Tertiary: blood-pressure/RAAS management to slow renal decline; meticulous skin care to prevent wound infections; audiologic rehabilitation.
  • Counseling: essential — 25% recurrence risk per pregnancy for carrier couples (autosomal recessive).

14. Other Species / Natural Disease

  • Taxonomy: Homo sapiens (NCBI Taxon 9606); experimental Mus musculus (10090) and Danio rerio (7955).
  • Orthologous genes: mouse Cd151 (NCBI Gene 12476); zebrafish cd151 ortholog.
  • Natural disease in other species: no well-documented spontaneous companion-animal analog identified in this investigation; the disease is characterized principally through engineered models.
  • Comparative biology: the integrin–laminin–tetraspanin adhesion mechanism is evolutionarily conserved, enabling faithful renal modeling in mouse and zebrafish (see Section 15).

15. Model Organisms

Model Type Phenotype recapitulation Limitations Ref
Cd151-null mouse (FVB) Mammalian knockout Massive proteinuria, FSGS, GBM disorganization, tubular cystic dilation; strain/BP-dependent Does NOT reproduce skin fragility or deafness PMID: 17015618, PMID: 22201679
Podocyte-specific Itga3 (α3) knockout Conditional mammalian Similar podocyte–GBM defects Integrin-partner surrogate PMID: 17015618
CRISPR-Cas9 zebrafish cd151 Vertebrate genome-edited Validated a novel human truncating variant as disease-causing Non-mammalian nephron architecture PMID: 35278129
  • Applications: dissecting podocyte adhesion, GBM assembly, blood-pressure/mechanosensitivity of nephropathy, and variant functional validation.
  • Resources: MGI (Cd151), ZFIN (zebrafish ortholog).

Mechanistic Model / Interpretation

The entire phenotype flows from a single principle: CD151 is a plasma-membrane organizer that stabilizes laminin-binding integrin adhesion complexes at basement-membrane interfaces. Tetraspanins are "master organizers" that laterally concentrate partner proteins into tetraspanin-enriched microdomains ([PMID: 29887866], [PMID: 22103505]); CD151 specifically corrals α3β1/α6β1/α6β4/α7β1 (PMID: 32667818). Remove CD151, and integrin–laminin adhesion loses strength and organization — the shared upstream lesion — after which the phenotype branches by tissue according to which epithelial cells depend most on this adhesion under load:

  • The kidney is the most sensitive organ because the glomerular filtration barrier operates under continuous hemodynamic stress; podocytes require robust α3β1–laminin adhesion to the GBM. This is why the mouse (lacking the human's skin/ear vulnerability) still develops severe nephropathy, and why blood pressure gates disease — a genuine gene × mechanical-environment interaction (PMID: 22201679, PMID: 35444113).
  • The skin blisters at mechanically stressed pretibial sites because α6β4 hemidesmosomes and α3β1 hybrid adhesions at the dermo-epidermal junction are destabilized (PMID: 31488507).
  • The inner ear develops sensorineural deafness through inferred cochlear basement-membrane defects — the least mechanistically demonstrated branch, since it is not modeled in mouse.

This model explains the disease's defining paradox (severe multi-organ human disease, kidney-only mouse) as a difference in tissue-specific redundancy and mechanical demand, not a difference in the core molecular defect.

Evidence Base

PMID Title (abbrev.) Role / Contribution
15265795 CD151... essential for basement membranes in kidney and skin Foundational: causal variant (insG383), triad, integrin complexes
17015618 Kidney failure in mice lacking CD151 Renal recapitulation; skin/ear model limitation
22201679 Blood pressure influences ESRD of Cd151 KO mice BP/modifier dependence; ACE-inhibition survival benefit
35278129 Basement membrane defects in CD151 glomerular disease Zebrafish variant validation; NGS screening argument
17565278 Tetraspan proteins: regulators of renal structure Mechanism: tetraspan-integrin perturbation disrupts glomerular selectivity
31488507 CD151 and α3β1 stabilize α6β4 adhesions Skin mechanism (hemidesmosome stabilization)
32667818 Update on the RAPH blood group system MER2/RAPH-null link; full integrin partner set (adds α7β1)
35519797 Syndromic EBS with nephropathy and epilepsy Expanded phenotype: epilepsy
38188895 Nephrotic syndrome, pretibial EB NS-EB-deafness syndrome; consanguineous case
35444113 TNS2-deficient nephropathy Frames CD151 nephropathy as mechanosensitive, modifier-gated
28615054 ESRD in EB — treatment options Feasibility of renal replacement therapy
24220332 ITGA3 R628P mutation Differential diagnosis; shared integrin-CD151 axis

Limitations and Knowledge Gaps

  1. Tiny evidence base: Fewer than ~20 molecularly confirmed patients; most clinical inference rests on a single index kindred plus scattered case reports. No natural-history cohort, prevalence estimate, or validated QoL data.
  2. Model–human discordance: The Cd151-null mouse reproduces nephropathy but not the skin or ear phenotype (PMID: 17015618). The deafness mechanism is therefore inferred, not demonstrated, and no faithful multi-organ model exists.
  3. Unidentified human modifier genes: Strain-dependence in mice implies human genetic modifiers of renal severity, but none are mapped — limiting prognostic prediction.
  4. β-thalassemia minor in the index kindred may reflect co-inheritance at 11p15.5 rather than a CD151-intrinsic effect; its consistency across unrelated cases is unclear.
  5. Therapeutics: RAAS-blockade benefit is extrapolated from mouse survival data; no human trial exists. No advanced (gene/cell) therapy has been attempted.
  6. Ontology mapping: Some suggested NCIT/UBERON/CL identifiers are best-match approximations pending curated verification.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry for CD151 deficiency to aggregate genotype–phenotype data, natural history, and outcomes across the world's scattered cases.
  2. Systematic reanalysis of undiagnosed nephrotic-syndrome/CKD cohorts with WES/WGS specifically interrogating CD151, given that it is not routinely screened (PMID: 35278129) — likely to reveal additional patients.
  3. Build a faithful multi-organ model (e.g., conditional/humanized mouse on a susceptible background, or cochlear organoids) to interrogate the deafness branch that current models miss.
  4. Test RAAS blockade prospectively (or via registry-based comparative effectiveness) in human patients to formally establish the nephroprotective benefit suggested by mouse data (PMID: 22201679).
  5. Map modifier loci via cross-strain QTL analysis in mice and, where feasible, human family studies, to explain variable renal severity.
  6. Explore gene-replacement feasibility (AAV or ex-vivo keratinocyte/podocyte approaches) given the clean monogenic LOF mechanism.
  7. Generate patient iPSC-derived podocyte and keratinocyte models to dissect integrin redistribution and adhesion-strength phenotypes and to screen candidate stabilizing compounds.

Report compiled from an autonomous multi-iteration investigation: 6 confirmed findings, 25 papers reviewed. Evidence types span human clinical case reports, mouse and zebrafish model organisms, and in vitro cell-adhesion studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 17
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 6
Terms named correctly 0
Terms named as a different term 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0000100 (1 mention) - the report calls it "Frequent"; HP calls it Nephrotic syndrome
  • HP:0000097 (1 mention) - the report calls it "Core (biopsy)"; HP calls it Focal segmental glomerulosclerosis
  • HP:0008404 (1 mention) - the report calls it "Frequent"; HP calls it Nail dystrophy
  • HP:0000407 (1 mention) - the report calls it "Core"; HP calls it Sensorineural hearing impairment
  • HP:0011904 (1 mention) - the report calls it "Index kindred"; HP calls it Persistence of hemoglobin F
  • HP:0001250 (1 mention) - the report calls it "Rare (expanded spectrum)"; HP calls it Seizure

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • UBERON:0002966 (obsolete regional part of midbrain tectum) (1 mention)