Retinitis Pigmentosa With or Without Situs Inversus

Mendelian MONDO:0014186 Pathograph 22 Show in embeddings browser Retinitis Pigmentosa

Retinitis pigmentosa with or without situs inversus (RP66) is an ultra-rare autosomal recessive ciliopathy caused by biallelic loss-of-function variants in ARL2BP, an effector of the small GTPases ARL2 and ARL3 that localises to the basal body and connecting cilium of photoreceptors. The disease is an unusually clean natural experiment in how one ciliary gene divides into organ-specific consequences. Rod-cone degeneration is present in every reported patient, because the photoreceptor outer segment is a modified primary cilium whose maintenance depends on continuous ARL2/ARL3-directed trafficking. The other manifestations follow the same protein's role in motile cilia, and each is variable: situs inversus totalis from failed left-right determination at the embryonic node, oligo- and asthenozoospermia from sperm flagellar defects, anosmia, and in one patient unilateral renal agenesis with microcysts. The disease name carries the variability in it. There is no proven disease-modifying therapy for retinitis pigmentosa. This entry deliberately carries no `treatments:` section: the supportive measures such a patient actually receives (low-vision rehabilitation, fertility counselling, surveillance for the extra-ocular features) are generic to syndromic retinal dystrophy and no source in this entry states them of RP66, so asserting them here would attach disease-specific claims to citations that do not make them. The gap is recorded as a discussion instead.

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1
Inheritance
6
Pathophys.
13
Phenotypes
3
Gaps
22
Pathograph
1
Genes
5
Variants
3
Differentials
2
Models
4
References
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive. Every reported family is consanguineous with a homozygous ARL2BP variant. Penetrance and expressivity pull apart by organ, which is why they are recorded separately here. The retinal disease is present in every reported biallelic patient, so penetrance is COMPLETE for the feature that defines the disease. The extra-ocular features are not: two sisters carrying a homozygous ARL2BP splice variant and affected by rod-cone dystrophy had no situs inversus on chest radiography. Recording a single INCOMPLETE value would understate the retinal arm and a single COMPLETE value would overstate the rest, so the disease-defining feature sets `penetrance` and the organ-to-organ variability sets `expressivity`.
Autosomal recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE
Show evidence (3 references)
PMID:23849777 SUPPORT Human Clinical
"Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."
States the inheritance mode, the gene, and the RP66 designation this entry uses as a synonym.
PMID:36507858 SUPPORT Human Clinical
"we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
An independent consanguineous family with a homozygous variant, consistent with recessive inheritance.
PMID:38649918 SUPPORT Human Clinical
"In these patients, chest radiographs did not show situs inversus but one of them, at the age of 36, had 20/200 BCVA in the RE and counting fingers in the LE with a visual field inferior to 10 degrees while her 27 years old sister, showed 20/25 BCVA in both eyes and visual field less than 30 degrees."
Two biallelic patients with the retinal disease and no situs inversus, which is the evidence for `expressivity: VARIABLE` rather than for incomplete penetrance of the disease itself.
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Discussions and Knowledge Gaps

3
Is there any therapy that alters the course of ARL2BP-related retinal degeneration, and what should be curated when the honest answer is no?
KNOWLEDGE GAP rp66_absence_of_disease_modifying_therapy
Attached to
treatments#
This entry has an empty `treatments:` section, and that is a finding rather than an omission. No therapy has been shown to modify the course of retinitis pigmentosa of any genotype, so there is nothing RP66-specific to curate; the best available statement is a Cochrane review's, and it is about RP as a class rather than about this gene. What patients receive is supportive care, which is not documented for RP66 anywhere in the cited literature. Curating it from general practice would manufacture disease-specific claims. If a heritable-retinal-dystrophy management guideline is added to the KB later, the supportive measures can be curated against it at `directness: INDIRECT`.
Show evidence (1 reference)
PMID:32573764 SUPPORT INDIRECT Human Clinical
"At this time, there is no proven therapy for RP."
A Cochrane review's summary of the therapeutic landscape. Graded INDIRECT because it is a statement about retinitis pigmentosa as a class, not about the ARL2BP subtype this entry describes.
Why is the retinal arm obligate while the motile-cilia arm is variable, if both follow from the same axonemal defect?
KNOWLEDGE GAP rp66_incomplete_penetrance_of_the_motile_cilia_arm
Attached to
pathophysiology#Motile Cilia and Flagellar Dysfunction phenotypes#Situs inversus totalis
Every reported ARL2BP patient has retinal degeneration; only some have situs inversus, and the disease name records that. If one protein is required for both primary and motile ciliary axonemes, the difference needs an explanation. Candidates include allele severity, the stochastic nature of nodal flow (where partial function gives randomised rather than reversed situs, so half of affected embryos would look normal), and redundancy in motile-cilia axoneme assembly that photoreceptors lack. None has been tested: no ARL2BP genotype-laterality correlation has been reported, and situs has not been scored in the knockout mouse in the source used here. The entry therefore models one shared upstream node branching into two arms, without asserting a reason for the asymmetry.
Proposed experiments
Nodal ciliary motility and laterality scoring in Arl2bp knockout embryos
rp66_nodal_cilia_in_arl2bp_ko
Score situs and nodal ciliary beat in a cohort of Arl2bp knockout embryos, to test whether laterality is randomised (stochastic nodal failure) or consistently reversed.
Readouts
Proportion of embryos with reversed situs
pathophysiology#Motile Cilia and Flagellar Dysfunction
Direction: ALTERED
Interpretation: Approximately half reversed would support stochastic nodal failure and explain the human variability without invoking allele severity.
Are the renal, olfactory and cryptorchidism findings features of RP66, or coincidences in consanguineous pedigrees?
KNOWLEDGE GAP rp66_phenotype_expanding_one_case_at_a_time
Attached to
phenotypes#Unilateral renal agenesis phenotypes#Renal cyst phenotypes#Anosmia
Renal agenesis, renal microcysts, cryptorchidism and anosmia each rest on a single patient, and every reported family is consanguineous, which is exactly the setting in which a second recessive condition can segregate unnoticed. The reporting authors are appropriately careful, describing these as expanding the manifestations rather than as established features, and one writes only that the patient "likely had olfactory dysfunction susceptibility". They are curated because a ciliopathy mechanism makes them plausible and because omitting them would hide real observations, but each is a single case and the entry does not assert a frequency for any of them.
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Pathophysiology

6
Biallelic ARL2BP Loss of Function
Reported alleles are homozygous and heterogeneous in class: a splice acceptor variant that alters pre-mRNA splicing demonstrably in blood RNA, a frameshift, and a missense substitution (p.Met45Arg) that reduces ARL2 binding. All converge on loss of ARL2BP function at the ciliary base.
Genetic context ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of ARL2BP from the Photoreceptor Basal Body and Connecting Cilium ARL2 anchors ARL2BP at the ciliary base; without binding, ARL2BP is not recruited.
Show evidence (2 references)
PMID:23849777 SUPPORT Human Clinical
"In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified."
The founding splice allele, with its effect demonstrated at the RNA level rather than predicted. The source contains a transposition, "ARLBP2" for ARL2BP, reproduced here rather than corrected.
PMID:23849777 SUPPORT In Vitro
"This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells."
Shows the missense allele acts by losing ARL2 binding and basal-body localisation, which is the functional definition of loss of function here.
Loss of ARL2BP from the Photoreceptor Basal Body and Connecting Cilium
ARL2BP normally localises to the basal body, the cilium-associated centriole and the periciliary extension of the photoreceptor inner segment. ARL2, not ARL3, is what recruits or anchors it there: depleting ARL2 displaces ARL2BP from the basal body while depleting ARL3 does not. That asymmetry is the reason this node names ARL2 specifically.
Photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology. Retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
Downstream
Defective Ciliary Axoneme and Doublet Microtubule Assembly ARL2BP at the ciliary base is required for normal axoneme structure and elongation.
Show evidence (2 references)
PMID:23849777 SUPPORT INDIRECT Model Organism
"In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment."
Establishes the normal localisation this node describes losing. Indirect because the localisation was mapped in mouse retina.
PMID:23849777 SUPPORT In Vitro
"Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium."
The experiment that distinguishes ARL2 from ARL3 as the anchoring partner, quoted with the authors' "suggesting".
Defective Ciliary Axoneme and Doublet Microtubule Assembly
The structural lesion. Depleting ARL2BP shortens cilia. In the knockout mouse retina, photoreceptor axonemes are shortened and the ciliary doublet microtubules are malformed, with open B-tubules and loss of the singlet microtubules. This is a defect in building the ciliary skeleton, not merely in cargo delivery along it.
axoneme assembly GO:0035082 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased axoneme assembly (GO:0035082). GO:0035082 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
ARL2BP patient dermal fibroblasts PRIMARY CELL CULTURE Patient fibroblasts show reduced ciliary length, the human cellular counterpart of the mouse axonemal defect.
Animal models
Arl2bp knockout mouse Mouse recapitulates The model is where the axonemal and doublet-microtubule lesion was characterised at all; the human evidence for this node is limited to shortened cilia in cultured cells.
Downstream
Photoreceptor Outer Segment Disorganization A shortened, malformed axoneme cannot template a normal outer segment.
Motile Cilia and Flagellar Dysfunction The same axonemal requirement applies to motile cilia at the embryonic node and to the sperm flagellum.
Show evidence (3 references)
PMID:23849777 SUPPORT In Vitro
"Depletion of ARL2BP caused cilia shortening."
The simplest direct demonstration that ARL2BP is needed to build a normal-length cilium.
PMID:29718757 SUPPORT Model Organism
"Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs."
The specific ultrastructural lesion in the axoneme, from the knockout mouse.
PMID:29718757 SUPPORT Model Organism
"On the basis of results from this study, we conclude that ARL2BP is necessary for photoreceptor ciliary doublet formation and axoneme elongation, which is required for OS morphogenesis and vision."
The authors' conclusion, which is exactly the causal claim this node and its downstream edge make.
Photoreceptor Outer Segment Disorganization
Outer segment disks are vertically aligned rather than stacked normally, and this is present before any photoreceptor is lost. Structure fails first; degeneration follows.
Retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
Downstream
Progressive Rod and Cone Photoreceptor Degeneration A photoreceptor that cannot maintain its outer segment does not survive.
Show evidence (1 reference)
PMID:29718757 SUPPORT Model Organism
"Before photoreceptor degeneration, we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes."
Establishes both the lesion and, importantly, that it precedes cell loss, which is what orders this node before the degeneration node.
Progressive Rod and Cone Photoreceptor Degeneration
Progressive loss of rods and then cones, producing the classic retinitis pigmentosa sequence of night blindness, peripheral field loss and finally central acuity loss. Progression can be slow: one patient retained useful residual vision at 63.
Photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
Animal models
Arl2bp knockout mouse Mouse recapitulates The mouse shows early and progressive loss of visual response, reproducing the human degeneration.
Downstream
Rod-cone dystrophy
Nyctalopia
Abnormal electroretinogram
Photophobia
Show evidence (2 references)
PMID:23849777 SUPPORT Human Clinical
"Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure."
Defines the degeneration process this node records.
PMID:29718757 SUPPORT Model Organism
"The KO mice display an early and progressive reduction in visual response."
The functional correlate of the degeneration in the knockout model.
Motile Cilia and Flagellar Dysfunction
The extra-ocular arm. The same axonemal requirement applies to the motile cilia of the embryonic node, which establish left-right asymmetry, and to the sperm flagellum. Unlike the retinal arm, these features are variable between patients, which is what the disease name records.
determination of left/right symmetry GO:0007368 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal determination of left/right symmetry (GO:0007368). GO:0007368 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Situs inversus totalis
Oligozoospermia
Abnormal sperm motility
Anosmia
Show evidence (2 references)
PMID:36507858 SUPPORT Human Clinical
"Situs inversus and male infertility have never been reported in the same patient with ARL2BP variants; therefore, this a novel ARL2BP-associated phenotypic triad of RP, situs inversus, and male infertility."
Establishes that the motile-cilia manifestations co-occur in a single patient, which is what licenses treating them as one mechanistic arm rather than separate associations.
PMID:36507858 SUPPORT In Vitro
"We found reduced patient-derived fibroblast proliferation and ciliary length."
Shortened cilia in the patient's own cells, linking the human phenotype to the ciliary lesion.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Retinitis Pigmentosa With or Without Situs Inversus Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Cardiovascular 1
Situs inversus totalis HP:0001696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Situs inversus totalis (HP:0001696). HP:0001696 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36507858 SUPPORT Human Clinical
"we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
Documents situs inversus totalis in an ARL2BP patient.
PMID:23849777 SUPPORT Human Clinical
"In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified."
Situs inversus in the founding family, the observation that put it in the disease name.
Eye 6
Rod-cone dystrophy OBLIGATE HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (HP:0000510), qualified as course progressive. HP:0000510 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:23849777 SUPPORT Human Clinical
"Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."
Establishes RP as the defining phenotype of the ARL2BP disorder.
PMID:38649918 SUPPORT Human Clinical
"This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
Independently reports the rod-cone dystrophy, using the rod-cone terminology this phenotype binds.
Constriction of peripheral visual field HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constriction of peripheral visual field (HP:0001133), qualified as course progressive. HP:0001133 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:38649918 SUPPORT Human Clinical
"Goldmann Visual Field showed a marked constriction in both eyes (< 10° with the V/4e target)"
Measured field constriction in the index patient at 49.
PMID:38649918 SUPPORT Human Clinical
"one of them, at the age of 36, had 20/200 BCVA in the RE and counting fingers in the LE with a visual field inferior to 10 degrees while her 27 years old sister, showed 20/25 BCVA in both eyes and visual field less than 30 degrees"
Independent family, and the source of the age-dependent spread noted in the description.
Spicular pigmentation of the retina HP:0007737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spicular pigmentation of the retina (HP:0007737). HP:0007737 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38649918 SUPPORT Human Clinical
"Fundus retinoscopy showed bone spicule pigmentation, attenuation of retinal vessels and pale optic disks"
Reports the finding in a second ARL2BP family.
PMID:38649918 SUPPORT Human Clinical
"a fundus characterized by attenuated vessels, rare bone spicule-like deposits scattered in mid-periphery and prominent patches of 360° chorioretinal nummular atrophy in far periphery"
The same finding in the index patient, described as spicule-like deposits.
Nyctalopia HP:0000662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nyctalopia (HP:0000662). HP:0000662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later."
Documents nyctalopia and the atypical symptom order this description notes.
Photophobia HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later."
Records photophobia as the presenting symptom in this patient.
Abnormal electroretinogram HP:0000512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal electroretinogram (HP:0000512). HP:0000512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy."
Records electroretinography as part of the phenotyping that established the retinal dystrophy.
Genitourinary 5
Oligozoospermia HP:0000798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligozoospermia (HP:0000798). HP:0000798 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36507858 SUPPORT Human Clinical
"we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
Documents oligozoospermia in an ARL2BP patient.
Abnormal sperm motility HP:0012206 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is asthenozoospermia, annotated with Abnormal sperm motility (HP:0012206). HP:0012206 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
Documents asthenozoospermia in an ARL2BP patient.
Unilateral renal agenesis HP:0000122 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Unilateral renal agenesis (HP:0000122). HP:0000122 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants."
States the finding and, in the same sentence, that it is new to the phenotype.
Renal cyst HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is renal microcysts, annotated with Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases."
Records the renal cysts and their diagnostic consequence.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants."
Records cryptorchidism as a newly reported feature.
Head and Neck 1
Anosmia HP:0000458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anosmia (HP:0000458). HP:0000458 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36507858 SUPPORT INDIRECT Human Clinical
"Moreover, this patient likely had olfactory dysfunction susceptibility and presented with anosmia."
The single observation. Graded INDIRECT because the authors write "likely had olfactory dysfunction susceptibility", which is a weaker claim than a phenotype attribution.
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Genetic Associations

1
ARL2BP
Gene: ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:23849777 SUPPORT Human Clinical
"Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."
Establishes the gene-disease relationship and ARL2BP's role as an ARL2/ARL3 effector.
PMID:23849777 SUPPORT In Vitro
"These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function."
Supports the notes claim that the functional partner is ARL2.
Variants (5)
c.101-1G>C (splice acceptor) Pathogenic
Gene: ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee.
Homozygous splice-acceptor variant in the founding RP-plus-situs-inversus family, shown to alter pre-mRNA splicing in blood RNA.
Show evidence (1 reference)
PMID:23849777 SUPPORT Human Clinical
"In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified."
Reports the allele and its splicing consequence. The gene symbol is misspelled "ARLBP2" in the source; the snippet reproduces it as published rather than correcting it.
c.134T>G (p.Met45Arg) Pathogenic
Gene: ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee.
The one missense allele, and the only one with a published mechanism at protein level: it reduces ARL2 binding and abolishes basal-body localisation, which is what ties the missense class to the same mislocalisation mechanism as the truncating alleles.
Show evidence (2 references)
PMID:23849777 SUPPORT Human Clinical
"In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified."
Reports the allele in the second founding family.
PMID:23849777 SUPPORT In Vitro
"the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells"
Establishes the functional consequence of this specific allele.
c.22_23delAG (p.S8Lfs*10) Pathogenic
Gene: ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee.
Frameshift allele in a Chinese consanguineous family, reported with the RP, situs inversus and male-infertility triad.
Show evidence (1 reference)
PMID:36507858 SUPPORT Human Clinical
"we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
Reports the allele and the phenotype it segregates with.
c.294-1G>C (splice acceptor, intron 4) Likely Pathogenic
Gene: ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee.
Splice-acceptor allele in the case with the longest published follow-up, and the one that added renal agenesis and microcysts to the phenotype.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4."
Reports the allele; graded LIKELY_PATHOGENIC because that is the classification the authors themselves assign.
c.100+1G>T (splice donor) Pathogenic
Gene: ARL2BP hgnc:17146 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in ARL2BP (hgnc:17146). hgnc:17146 is a gene from the HUGO Gene Nomenclature Committee.
Novel splice-donor allele from a consanguineous Pakistani family, absent from gnomAD and ClinVar, with SpliceAI supporting loss of both the acceptor and the donor site.
Show evidence (2 references)
PMID:40384762 SUPPORT Human Clinical
"In family RP067, a novel splice site variant of the ARL2BP gene was found to be segregated with the RP and situs inversus phenotype in a recessive manner"
Reports the allele segregating with the disease.
PMID:40384762 SUPPORT Computational
"This variant is likely to affect splicing, with Splice AI scores of 0.96 for acceptors loss and 0.99 for donor loss. This variant is absent from gnomAD (v.2.1.1) and other databases including ClinVar."
In silico splicing prediction and population-database absence; graded COMPUTATIONAL because that is what the sentence reports.
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External Assertions

1
OMIM phenotype record for retinitis pigmentosa 66
OMIM disease record OMIM:615434
The RP66 *phenotype* MIM, which is what MONDO:0014186 xrefs. Recorded explicitly because the neighbouring ARL2BP *gene* MIM is 615407 and the two are easy to transpose; the citation below states both with their roles.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"biallelic pathogenic variants in ARL2BP (OMIM *615,407) can cause autosomal recessive Retinitis Pigmentosa (arRP) with or without situs inversus (OMIM #615,434)"
Names the gene MIM and the phenotype MIM in one sentence, with the asterisk and hash prefixes that mark which is which. Quoted as published, including the thousands separators the journal used in the MIM numbers.
🔬

Diagnosis

1
Ophthalmic phenotyping with next-generation sequencing
Retinal phenotyping (electroretinography, full-field stimulus threshold, multimodal imaging) establishes the dystrophy; sequencing establishes the gene. The extra-ocular features are what should prompt looking at ARL2BP specifically rather than a generic RP panel result: a patient with RP plus situs inversus is a very short differential.
Show evidence (2 references)
PMID:38649918 SUPPORT Human Clinical
"Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy."
Names the phenotyping modalities that establish the retinal diagnosis.
PMID:38649918 SUPPORT Human Clinical
"Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4."
The molecular confirmation step, in a real diagnostic sequence.
📈

Progression

3
Symptomatic onset in early adulthood
Age: Around 20 years
The reported opening symptoms are not the classic ones. In the longest-followed case photophobia and episodes of photopsia came first, a decade before night blindness.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"preceded by photophobia and episodes of photopsia already noted ten years before"
Places photophobia and photopsia a decade ahead of night blindness.
Night blindness, field constriction and diagnosis
Age: 30 to 39 years
Night blindness and visual field constriction begin around 30 and become prominent at 35; molecular diagnosis followed at 32 in this case, and driving stopped at 39.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The patient reported a history of night blindness (NB) and visual field constriction (VFC) since he was 30 years old, preceded by photophobia and episodes of photopsia already noted ten years before. Diagnosis of arRP was made when he was 32 years old and both NB and VFC became prominent at 35,..."
The staged natural history for this phase, including age at diagnosis.
Advanced retinal degeneration with retained residual vision
Age: 49 to 63 years
Acuity reaches 20/200 with fields under 10 degrees by 49, yet useful residual vision persists into the seventh decade. The slow tail matters clinically: it is the window any future therapy would have to act in.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"When he was 49 years old, visual acuity was 20/200 in both eyes with a fundus characterized by attenuated vessels, rare bone spicule-like deposits scattered in mid-periphery and prominent patches of 360° chorioretinal nummular atrophy in far periphery."
Establishes the level of impairment at 49.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
A handful of largely consanguineous families. Two in the founding report, with further single-patient reports since. No population-level prevalence estimate exists for the ARL2BP subtype; the figure below is a diagnostic yield within one consanguineous inherited-retinal-dystrophy cohort, not a population rate, which is why this record stays CASES_IN_LITERATURE rather than carrying a `rate_per_100000`.
Show evidence (1 reference)
PMID:40384762 SUPPORT Human Clinical
"Causative variants in previously reported syndromic IRDs genes were detected in 13/72 (18%) IRD families, including 5/72 (6.94%), 4/72 (5.55%), 2/72 (2.8%), 1/72(1.38%) and 1/72 (1.38%) in Usher syndrome, Bardet-Biedl syndrome, Batten disease, retinitis pigmentosa with situs inversus and..."
One family in 72 in a consanguineous Pakistani IRD cohort, the only cohort-denominated frequency available for this disease. It bounds how rare the entity is among inherited retinal dystrophy referrals; it is not a population prevalence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Retinitis Pigmentosa With or Without Situs Inversus:

Senior-Loken, Bardet-Biedl and Joubert syndromes
Overlapping Features All are ciliopathies combining retinal dystrophy with renal disease, and the renal cysts reported in one ARL2BP patient put them directly in the frame. The authors who reported that patient say so explicitly.
Show evidence (1 reference)
PMID:38649918 SUPPORT Human Clinical
"The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases."
Names this differential and its trigger.
Primary ciliary dyskinesia
Overlapping Features Shares situs inversus and male infertility from motile ciliary dysfunction. Retinal degeneration is not a feature of PCD, so the retinal arm separates them.
Non-syndromic autosomal recessive retinitis pigmentosa
Overlapping Features RP66 will look non-syndromic in any patient without situs inversus, which is roughly what "with or without situs inversus" means. Separating them requires asking about laterality, fertility and renal anatomy, none of which an ophthalmic workup covers.
🧫

Experimental Models

1
ARL2BP patient dermal fibroblasts PRIMARY_CELL_CULTURE
Fibroblasts from the patient with the RP, situs inversus and oligozoospermia triad. Valuable because they demonstrate the ciliary lesion in the patient's own cells rather than by knockdown or in mouse.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:36507858
Pathograph links
Defective Ciliary Axoneme and Doublet Microtubule Assembly recapitulates fidelity: moderate observes: cellular Patient fibroblasts show reduced ciliary length, the human cellular counterpart of the mouse axonemal defect.
Limitations: Fibroblast primary cilia are not photoreceptor connecting cilia, so ciliary length in this system is a proxy for, not a measurement of, the retinal lesion. Reduced proliferation was measured in the same cells and could confound a length measurement made across a cycling population.
Readouts
Primary cilium length
Direction: DECREASED
Interpretation: Shorter cilia in patient-derived cells, consistent with the knockdown and knockout results.
Show evidence (1 reference)
PMID:36507858 SUPPORT In Vitro
"We found reduced patient-derived fibroblast proliferation and ciliary length."
The measurement, and the proliferation result that the limitations field flags as a possible confounder.
Show evidence (1 reference)
PMID:36507858 SUPPORT In Vitro
"Our findings expand the genotypic spectrum and reveal abnormal cell proliferation and ciliogenesis in ARL2BP-associated patients."
The authors' summary of what the patient cells show, which is the basis for treating them as informative for the ciliary node.
🐁

Animal Models

1
Arl2bp knockout mouse
Constitutive Arl2bp knockout generated specifically to ask how a ciliary protein contributes to outer segment formation. It gives the structural detail that human tissue cannot: axoneme length, disk orientation, and doublet microtubule architecture.
Species
Mouse
Genotype
Arl2bp knockout, homozygous
Publication
PMID:29718757
Pathograph links
Defective Ciliary Axoneme and Doublet Microtubule Assembly recapitulates fidelity: high observes: cellular The model is where the axonemal and doublet-microtubule lesion was characterised at all; the human evidence for this node is limited to shortened cilia in cultured cells.
Limitations: A constitutive knockout, whereas the reported human alleles include a missense substitution that reduces rather than abolishes ARL2 binding, so the mouse likely models the severe end of the allelic spectrum. The mouse is also not reported here to show situs inversus or infertility, so it speaks only to the retinal arm.
Readouts
Photoreceptor axoneme length and doublet microtubule architecture
Direction: ALTERED
Interpretation: Shortened axonemes with open B-tubules and absent singlets, the structural lesion this node asserts.
Show evidence (1 reference)
PMID:29718757 SUPPORT Model Organism
"Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs."
The measurement behind this readout.
Show evidence (1 reference)
PMID:29718757 SUPPORT Model Organism
"To investigate how ciliary proteins contribute to OS formation, we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa."
States that the model was made for this human disease, which is what licenses treating it as informative for these nodes.
Progressive Rod and Cone Photoreceptor Degeneration recapitulates fidelity: moderate observes: organism The mouse shows early and progressive loss of visual response, reproducing the human degeneration.
Limitations: Rate and endpoint are not comparable: the mouse declines early, whereas one human patient retained useful residual vision at 63. Mouse retina also lacks a macula, so the central-acuity loss that dominates late human disease has no counterpart.
Readouts
Visual response amplitude
Direction: DECREASED
Interpretation: Functional readout of photoreceptor loss over time.
Show evidence (1 reference)
PMID:29718757 SUPPORT Model Organism
"The KO mice display an early and progressive reduction in visual response."
The measurement and its direction.
{ }

Source YAML

click to show 
name: Retinitis Pigmentosa With or Without Situs Inversus
creation_date: "2026-09-06T19:15:00Z"
category: Mendelian
description: >-
  Retinitis pigmentosa with or without situs inversus (RP66) is an ultra-rare
  autosomal recessive ciliopathy caused by biallelic loss-of-function variants
  in ARL2BP, an effector of the small GTPases ARL2 and ARL3 that localises to
  the basal body and connecting cilium of photoreceptors.

  The disease is an unusually clean natural experiment in how one ciliary gene
  divides into organ-specific consequences. Rod-cone degeneration is present in
  every reported patient, because the photoreceptor outer segment is a modified
  primary cilium whose maintenance depends on continuous ARL2/ARL3-directed
  trafficking. The other manifestations follow the same protein's role in
  motile cilia, and each is variable: situs inversus totalis from failed
  left-right determination at the embryonic node, oligo- and asthenozoospermia
  from sperm flagellar defects, anosmia, and in one patient unilateral renal
  agenesis with microcysts. The disease name carries the variability in it.

  There is no proven disease-modifying therapy for retinitis pigmentosa. This
  entry deliberately carries no `treatments:` section: the supportive measures
  such a patient actually receives (low-vision rehabilitation, fertility
  counselling, surveillance for the extra-ocular features) are generic to
  syndromic retinal dystrophy and no source in this entry states them of RP66,
  so asserting them here would attach disease-specific claims to citations that
  do not make them. The gap is recorded as a discussion instead.
disease_term:
  preferred_term: retinitis pigmentosa with or without situs inversus
  term:
    id: MONDO:0014186
    label: retinitis pigmentosa with or without situs inversus
synonyms:
- RP66
- ARL2BP-related retinitis pigmentosa
- ARL2BP-related rod-cone dystrophy
parents:
- Retinitis Pigmentosa
references:
- reference: PMID:23849777
  title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
  findings: []
- reference: PMID:29718757
  title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
  findings: []
- reference: PMID:36507858
  title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
  findings: []
- reference: PMID:38649918
  title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
  findings: []
external_assertions:
- name: OMIM phenotype record for retinitis pigmentosa 66
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:615434
  description: >-
    The RP66 *phenotype* MIM, which is what MONDO:0014186 xrefs. Recorded
    explicitly because the neighbouring ARL2BP *gene* MIM is 615407 and the two
    are easy to transpose; the citation below states both with their roles.
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in ARL2BP (OMIM *615,407) can cause autosomal recessive Retinitis Pigmentosa (arRP) with or without situs inversus (OMIM #615,434)"
    explanation: >-
      Names the gene MIM and the phenotype MIM in one sentence, with the
      asterisk and hash prefixes that mark which is which. Quoted as published,
      including the thousands separators the journal used in the MIM numbers.
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive. Every reported family is consanguineous with a
    homozygous ARL2BP variant.

    Penetrance and expressivity pull apart by organ, which is why they are
    recorded separately here. The retinal disease is present in every reported
    biallelic patient, so penetrance is COMPLETE for the feature that defines
    the disease. The extra-ocular features are not: two sisters carrying a
    homozygous ARL2BP splice variant and affected by rod-cone dystrophy had no
    situs inversus on chest radiography. Recording a single INCOMPLETE value
    would understate the retinal arm and a single COMPLETE value would
    overstate the rest, so the disease-defining feature sets `penetrance` and
    the organ-to-organ variability sets `expressivity`.
  penetrance: COMPLETE
  expressivity: VARIABLE
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."
    explanation: >-
      States the inheritance mode, the gene, and the RP66 designation this
      entry uses as a synonym.
  - reference: PMID:36507858
    reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
    explanation: >-
      An independent consanguineous family with a homozygous variant,
      consistent with recessive inheritance.
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, chest radiographs did not show situs inversus but one of them, at the age of 36, had 20/200 BCVA in the RE and counting fingers in the LE with a visual field inferior to 10 degrees while her 27 years old sister, showed 20/25 BCVA in both eyes and visual field less than 30 degrees."
    explanation: >-
      Two biallelic patients with the retinal disease and no situs inversus,
      which is the evidence for `expressivity: VARIABLE` rather than for
      incomplete penetrance of the disease itself.
pathophysiology:
- name: Biallelic ARL2BP Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Reported alleles are homozygous and heterogeneous in class: a splice
    acceptor variant that alters pre-mRNA splicing demonstrably in blood RNA, a
    frameshift, and a missense substitution (p.Met45Arg) that reduces ARL2
    binding. All converge on loss of ARL2BP function at the ciliary base.
  genetic_context:
    gene:
      preferred_term: ARL2BP
      term:
        id: hgnc:17146
        label: ARL2BP
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified."
    explanation: >-
      The founding splice allele, with its effect demonstrated at the RNA level
      rather than predicted. The source contains a transposition, "ARLBP2" for
      ARL2BP, reproduced here rather than corrected.
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells."
    explanation: >-
      Shows the missense allele acts by losing ARL2 binding and basal-body
      localisation, which is the functional definition of loss of function
      here.
  downstream:
  - target: Loss of ARL2BP from the Photoreceptor Basal Body and Connecting Cilium
    description: >-
      ARL2 anchors ARL2BP at the ciliary base; without binding, ARL2BP is not
      recruited.
- name: Loss of ARL2BP from the Photoreceptor Basal Body and Connecting Cilium
  biological_scale: MOLECULAR
  description: >-
    ARL2BP normally localises to the basal body, the cilium-associated
    centriole and the periciliary extension of the photoreceptor inner segment.
    ARL2, not ARL3, is what recruits or anchors it there: depleting ARL2
    displaces ARL2BP from the basal body while depleting ARL3 does not. That
    asymmetry is the reason this node names ARL2 specifically.
  cell_types:
  - preferred_term: Photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: Retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment."
    explanation: >-
      Establishes the normal localisation this node describes losing. Indirect
      because the localisation was mapped in mouse retina.
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium."
    explanation: >-
      The experiment that distinguishes ARL2 from ARL3 as the anchoring
      partner, quoted with the authors' "suggesting".
  downstream:
  - target: Defective Ciliary Axoneme and Doublet Microtubule Assembly
    description: >-
      ARL2BP at the ciliary base is required for normal axoneme structure and
      elongation.
- name: Defective Ciliary Axoneme and Doublet Microtubule Assembly
  biological_scale: CELLULAR
  description: >-
    The structural lesion. Depleting ARL2BP shortens cilia. In the knockout
    mouse retina, photoreceptor axonemes are shortened and the ciliary doublet
    microtubules are malformed, with open B-tubules and loss of the singlet
    microtubules. This is a defect in building the ciliary skeleton, not merely
    in cargo delivery along it.
  biological_processes:
  - preferred_term: axoneme assembly
    term:
      id: GO:0035082
      label: axoneme assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Depletion of ARL2BP caused cilia shortening."
    explanation: >-
      The simplest direct demonstration that ARL2BP is needed to build a
      normal-length cilium.
  - reference: PMID:29718757
    reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs."
    explanation: >-
      The specific ultrastructural lesion in the axoneme, from the knockout
      mouse.
  - reference: PMID:29718757
    reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "On the basis of results from this study, we conclude that ARL2BP is necessary for photoreceptor ciliary doublet formation and axoneme elongation, which is required for OS morphogenesis and vision."
    explanation: >-
      The authors' conclusion, which is exactly the causal claim this node and
      its downstream edge make.
  downstream:
  - target: Photoreceptor Outer Segment Disorganization
    description: >-
      A shortened, malformed axoneme cannot template a normal outer segment.
  - target: Motile Cilia and Flagellar Dysfunction
    description: >-
      The same axonemal requirement applies to motile cilia at the embryonic
      node and to the sperm flagellum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Photoreceptor Outer Segment Disorganization
  biological_scale: CELLULAR
  description: >-
    Outer segment disks are vertically aligned rather than stacked normally,
    and this is present before any photoreceptor is lost. Structure fails
    first; degeneration follows.
  cell_types:
  - preferred_term: Retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  evidence:
  - reference: PMID:29718757
    reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Before photoreceptor degeneration, we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes."
    explanation: >-
      Establishes both the lesion and, importantly, that it precedes cell loss,
      which is what orders this node before the degeneration node.
  downstream:
  - target: Progressive Rod and Cone Photoreceptor Degeneration
    description: >-
      A photoreceptor that cannot maintain its outer segment does not survive.
- name: Progressive Rod and Cone Photoreceptor Degeneration
  biological_scale: TISSUE
  description: >-
    Progressive loss of rods and then cones, producing the classic retinitis
    pigmentosa sequence of night blindness, peripheral field loss and finally
    central acuity loss. Progression can be slow: one patient retained useful
    residual vision at 63.
  cell_types:
  - preferred_term: Photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure."
    explanation: >-
      Defines the degeneration process this node records.
  - reference: PMID:29718757
    reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The KO mice display an early and progressive reduction in visual response."
    explanation: >-
      The functional correlate of the degeneration in the knockout model.
  downstream:
  - target: Rod-cone dystrophy
  - target: Nyctalopia
  - target: Abnormal electroretinogram
  - target: Photophobia
- name: Motile Cilia and Flagellar Dysfunction
  biological_scale: CELLULAR
  description: >-
    The extra-ocular arm. The same axonemal requirement applies to the motile
    cilia of the embryonic node, which establish left-right asymmetry, and to
    the sperm flagellum. Unlike the retinal arm, these features are variable
    between patients, which is what the disease name records.
  biological_processes:
  - preferred_term: determination of left/right symmetry
    term:
      id: GO:0007368
      label: determination of left/right symmetry
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36507858
    reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Situs inversus and male infertility have never been reported in the same patient with ARL2BP variants; therefore, this a novel ARL2BP-associated phenotypic triad of RP, situs inversus, and male infertility."
    explanation: >-
      Establishes that the motile-cilia manifestations co-occur in a single
      patient, which is what licenses treating them as one mechanistic arm
      rather than separate associations.
  - reference: PMID:36507858
    reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found reduced patient-derived fibroblast proliferation and ciliary length."
    explanation: >-
      Shortened cilia in the patient's own cells, linking the human phenotype
      to the ciliary lesion.
  downstream:
  - target: Situs inversus totalis
  - target: Oligozoospermia
  - target: Abnormal sperm motility
  - target: Anosmia
phenotypes:
- category: Ocular
  name: Rod-cone dystrophy
  frequency: OBLIGATE
  description: >-
    Retinitis pigmentosa, present in every reported patient. Tagged OBLIGATE
    because it is the one feature the disease definition requires; the disease
    name makes everything else optional.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."
    explanation: >-
      Establishes RP as the defining phenotype of the ARL2BP disorder.
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    explanation: >-
      Independently reports the rod-cone dystrophy, using the rod-cone
      terminology this phenotype binds.
- category: Ocular
  name: Constriction of peripheral visual field
  description: >-
    The functional hallmark of the retinal arm, and the measure that tracks
    progression. In the long-followed case the field was already prominent as a
    symptom at 35 and had narrowed to under 10 degrees by 49; two affected
    sisters in a separate family measured under 10 and under 30 degrees at 36
    and 27 respectively, which is the spread this phenotype covers.
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Goldmann Visual Field showed a marked constriction in both eyes (< 10° with the V/4e target)"
    explanation: >-
      Measured field constriction in the index patient at 49.
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one of them, at the age of 36, had 20/200 BCVA in the RE and counting fingers in the LE with a visual field inferior to 10 degrees while her 27 years old sister, showed 20/25 BCVA in both eyes and visual field less than 30 degrees"
    explanation: >-
      Independent family, and the source of the age-dependent spread noted in
      the description.
- category: Ocular
  name: Spicular pigmentation of the retina
  description: >-
    Bone-spicule pigmentation, the fundus finding that is close to definitional
    for retinitis pigmentosa and is reported across ARL2BP families. It appears
    alongside attenuated retinal vessels and optic disc pallor.
  phenotype_term:
    preferred_term: Spicular pigmentation of the retina
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fundus retinoscopy showed bone spicule pigmentation, attenuation of retinal vessels and pale optic disks"
    explanation: >-
      Reports the finding in a second ARL2BP family.
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a fundus characterized by attenuated vessels, rare bone spicule-like deposits scattered in mid-periphery and prominent patches of 360° chorioretinal nummular atrophy in far periphery"
    explanation: >-
      The same finding in the index patient, described as spicule-like deposits.
- category: Ocular
  name: Nyctalopia
  description: >-
    Night blindness. Note the reported order of symptoms is not always the
    classic one: in the long-followed case, photophobia came first at 20 and
    nyctalopia ten years later.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later."
    explanation: >-
      Documents nyctalopia and the atypical symptom order this description
      notes.
- category: Ocular
  name: Photophobia
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later."
    explanation: >-
      Records photophobia as the presenting symptom in this patient.
- category: Ocular
  name: Abnormal electroretinogram
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy."
    explanation: >-
      Records electroretinography as part of the phenotyping that established
      the retinal dystrophy.
- category: Laterality
  name: Situs inversus totalis
  description: >-
    Complete mirror-image reversal of thoracic and abdominal viscera, from
    failed left-right determination at the embryonic node. Present in some
    patients and absent in others, which is the variability the disease name
    records.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  evidence:
  - reference: PMID:36507858
    reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
    explanation: >-
      Documents situs inversus totalis in an ARL2BP patient.
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified."
    explanation: >-
      Situs inversus in the founding family, the observation that put it in the
      disease name.
- category: Reproductive
  name: Oligozoospermia
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:36507858
    reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
    explanation: >-
      Documents oligozoospermia in an ARL2BP patient.
- category: Reproductive
  name: Abnormal sperm motility
  description: >-
    Asthenozoospermia, reported in a second patient. Bound to the motility
    parent term because HPO has no separate asthenozoospermia class.
  phenotype_term:
    preferred_term: asthenozoospermia
    term:
      id: HP:0012206
      label: Abnormal sperm motility
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    explanation: >-
      Documents asthenozoospermia in an ARL2BP patient.
- category: Neurologic
  name: Anosmia
  description: >-
    Reported in one patient, and framed cautiously by the reporting authors as
    a susceptibility rather than an established feature.
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: PMID:36507858
    reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Moreover, this patient likely had olfactory dysfunction susceptibility and presented with anosmia."
    explanation: >-
      The single observation. Graded INDIRECT because the authors write "likely
      had olfactory dysfunction susceptibility", which is a weaker claim than a
      phenotype attribution.
- category: Renal
  name: Unilateral renal agenesis
  description: >-
    Reported in one patient and described by its authors as expanding the
    clinical manifestations of ARL2BP variants, that is, as a new feature
    rather than a known one.
  phenotype_term:
    preferred_term: Unilateral renal agenesis
    term:
      id: HP:0000122
      label: Unilateral renal agenesis
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants."
    explanation: >-
      States the finding and, in the same sentence, that it is new to the
      phenotype.
- category: Renal
  name: Renal cyst
  description: >-
    Renal microcysts in the same patient. Clinically consequential out of
    proportion to their size: their presence is what forces a differential
    against Senior-Loken, Bardet-Biedl and Joubert syndromes.
  phenotype_term:
    preferred_term: renal microcysts
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases."
    explanation: >-
      Records the renal cysts and their diagnostic consequence.
- category: Reproductive
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants."
    explanation: >-
      Records cryptorchidism as a newly reported feature.
genetic:
- name: ARL2BP
  gene_term:
    preferred_term: ARL2BP
    term:
      id: hgnc:17146
      label: ARL2BP
  relationship_type: CAUSATIVE
  notes: >-
    ARL2BP is an effector of ARL2 and ARL3. Functionally it is ARL2 that
    anchors it at the ciliary base: ARL3 depletion does not displace it. That
    matters when reading the wider ARL2/ARL3 photoreceptor-trafficking
    literature, much of which concerns ARL3 and its GAP RP2 in a different
    disease.
  variants:
  - name: c.101-1G>C (splice acceptor)
    description: >-
      Homozygous splice-acceptor variant in the founding RP-plus-situs-inversus
      family, shown to alter pre-mRNA splicing in blood RNA.
    gene:
      preferred_term: ARL2BP
      term:
        id: hgnc:17146
        label: ARL2BP
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:23849777
      reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified."
      explanation: >-
        Reports the allele and its splicing consequence. The gene symbol is
        misspelled "ARLBP2" in the source; the snippet reproduces it as
        published rather than correcting it.
  - name: c.134T>G (p.Met45Arg)
    description: >-
      The one missense allele, and the only one with a published mechanism at
      protein level: it reduces ARL2 binding and abolishes basal-body
      localisation, which is what ties the missense class to the same
      mislocalisation mechanism as the truncating alleles.
    gene:
      preferred_term: ARL2BP
      term:
        id: hgnc:17146
        label: ARL2BP
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:23849777
      reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified."
      explanation: >-
        Reports the allele in the second founding family.
    - reference: PMID:23849777
      reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells"
      explanation: >-
        Establishes the functional consequence of this specific allele.
  - name: c.22_23delAG (p.S8Lfs*10)
    description: >-
      Frameshift allele in a Chinese consanguineous family, reported with the
      RP, situs inversus and male-infertility triad.
    gene:
      preferred_term: ARL2BP
      term:
        id: hgnc:17146
        label: ARL2BP
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:36507858
      reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia"
      explanation: >-
        Reports the allele and the phenotype it segregates with.
  - name: c.294-1G>C (splice acceptor, intron 4)
    description: >-
      Splice-acceptor allele in the case with the longest published follow-up,
      and the one that added renal agenesis and microcysts to the phenotype.
    gene:
      preferred_term: ARL2BP
      term:
        id: hgnc:17146
        label: ARL2BP
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:38649918
      reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4."
      explanation: >-
        Reports the allele; graded LIKELY_PATHOGENIC because that is the
        classification the authors themselves assign.
  - name: c.100+1G>T (splice donor)
    description: >-
      Novel splice-donor allele from a consanguineous Pakistani family,
      absent from gnomAD and ClinVar, with SpliceAI supporting loss of both
      the acceptor and the donor site.
    gene:
      preferred_term: ARL2BP
      term:
        id: hgnc:17146
        label: ARL2BP
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:40384762
      reference_title: "Syndromic forms of inherited retinal dystrophies: a comprehensive molecular diagnosis of consanguineous Pakistani families using capture panel sequencing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In family RP067, a novel splice site variant of the ARL2BP gene was found to be segregated with the RP and situs inversus phenotype in a recessive manner"
      explanation: >-
        Reports the allele segregating with the disease.
    - reference: PMID:40384762
      reference_title: "Syndromic forms of inherited retinal dystrophies: a comprehensive molecular diagnosis of consanguineous Pakistani families using capture panel sequencing."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "This variant is likely to affect splicing, with Splice AI scores of 0.96 for acceptors loss and 0.99 for donor loss. This variant is absent from gnomAD (v.2.1.1) and other databases including ClinVar."
      explanation: >-
        In silico splicing prediction and population-database absence; graded
        COMPUTATIONAL because that is what the sentence reports.
  evidence:
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."
    explanation: >-
      Establishes the gene-disease relationship and ARL2BP's role as an
      ARL2/ARL3 effector.
  - reference: PMID:23849777
    reference_title: "Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function."
    explanation: >-
      Supports the notes claim that the functional partner is ARL2.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A handful of largely consanguineous families. Two in the founding report,
    with further single-patient reports since. No population-level prevalence
    estimate exists for the ARL2BP subtype; the figure below is a diagnostic
    yield within one consanguineous inherited-retinal-dystrophy cohort, not a
    population rate, which is why this record stays CASES_IN_LITERATURE rather
    than carrying a `rate_per_100000`.
  evidence:
  - reference: PMID:40384762
    reference_title: "Syndromic forms of inherited retinal dystrophies: a comprehensive molecular diagnosis of consanguineous Pakistani families using capture panel sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Causative variants in previously reported syndromic IRDs genes were detected in 13/72 (18%) IRD families, including 5/72 (6.94%), 4/72 (5.55%), 2/72 (2.8%), 1/72(1.38%) and 1/72 (1.38%) in Usher syndrome, Bardet-Biedl syndrome, Batten disease, retinitis pigmentosa with situs inversus and Stickler syndrome segregated families, respectively."
    explanation: >-
      One family in 72 in a consanguineous Pakistani IRD cohort, the only
      cohort-denominated frequency available for this disease. It bounds how
      rare the entity is among inherited retinal dystrophy referrals; it is not
      a population prevalence.
animal_models:
- name: Arl2bp knockout mouse
  species: Mouse
  genotype: Arl2bp knockout, homozygous
  publication: PMID:29718757
  description: >-
    Constitutive Arl2bp knockout generated specifically to ask how a ciliary
    protein contributes to outer segment formation. It gives the structural
    detail that human tissue cannot: axoneme length, disk orientation, and
    doublet microtubule architecture.
  modeled_mechanisms:
  - target: Defective Ciliary Axoneme and Doublet Microtubule Assembly
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The model is where the axonemal and doublet-microtubule lesion was
      characterised at all; the human evidence for this node is limited to
      shortened cilia in cultured cells.
    limitations: >-
      A constitutive knockout, whereas the reported human alleles include a
      missense substitution that reduces rather than abolishes ARL2 binding, so
      the mouse likely models the severe end of the allelic spectrum. The mouse
      is also not reported here to show situs inversus or infertility, so it
      speaks only to the retinal arm.
    readouts:
    - name: Photoreceptor axoneme length and doublet microtubule architecture
      target: Defective Ciliary Axoneme and Doublet Microtubule Assembly
      direction: ALTERED
      interpretation: >-
        Shortened axonemes with open B-tubules and absent singlets, the
        structural lesion this node asserts.
      evidence:
      - reference: PMID:29718757
        reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs."
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:29718757
      reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To investigate how ciliary proteins contribute to OS formation, we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa."
      explanation: >-
        States that the model was made for this human disease, which is what
        licenses treating it as informative for these nodes.
  - target: Progressive Rod and Cone Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The mouse shows early and progressive loss of visual response,
      reproducing the human degeneration.
    limitations: >-
      Rate and endpoint are not comparable: the mouse declines early, whereas
      one human patient retained useful residual vision at 63. Mouse retina
      also lacks a macula, so the central-acuity loss that dominates late human
      disease has no counterpart.
    readouts:
    - name: Visual response amplitude
      target: Progressive Rod and Cone Photoreceptor Degeneration
      direction: DECREASED
      interpretation: >-
        Functional readout of photoreceptor loss over time.
      evidence:
      - reference: PMID:29718757
        reference_title: "ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The KO mice display an early and progressive reduction in visual response."
        explanation: >-
          The measurement and its direction.
experimental_models:
- name: ARL2BP patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Fibroblasts from the patient with the RP, situs inversus and oligozoospermia
    triad. Valuable because they demonstrate the ciliary lesion in the
    patient's own cells rather than by knockdown or in mouse.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:36507858
  modeled_mechanisms:
  - target: Defective Ciliary Axoneme and Doublet Microtubule Assembly
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Patient fibroblasts show reduced ciliary length, the human cellular
      counterpart of the mouse axonemal defect.
    limitations: >-
      Fibroblast primary cilia are not photoreceptor connecting cilia, so
      ciliary length in this system is a proxy for, not a measurement of, the
      retinal lesion. Reduced proliferation was measured in the same cells and
      could confound a length measurement made across a cycling population.
    readouts:
    - name: Primary cilium length
      target: Defective Ciliary Axoneme and Doublet Microtubule Assembly
      direction: DECREASED
      interpretation: >-
        Shorter cilia in patient-derived cells, consistent with the knockdown
        and knockout results.
      evidence:
      - reference: PMID:36507858
        reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We found reduced patient-derived fibroblast proliferation and ciliary length."
        explanation: >-
          The measurement, and the proliferation result that the limitations
          field flags as a possible confounder.
    evidence:
    - reference: PMID:36507858
      reference_title: "Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our findings expand the genotypic spectrum and reveal abnormal cell proliferation and ciliogenesis in ARL2BP-associated patients."
      explanation: >-
        The authors' summary of what the patient cells show, which is the basis
        for treating them as informative for the ciliary node.
progression:
- phase: Symptomatic onset in early adulthood
  age_range: Around 20 years
  notes: >-
    The reported opening symptoms are not the classic ones. In the
    longest-followed case photophobia and episodes of photopsia came first, a
    decade before night blindness.
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "preceded by photophobia and episodes of photopsia already noted ten years before"
    explanation: >-
      Places photophobia and photopsia a decade ahead of night blindness.
- phase: Night blindness, field constriction and diagnosis
  age_range: 30 to 39 years
  notes: >-
    Night blindness and visual field constriction begin around 30 and become
    prominent at 35; molecular diagnosis followed at 32 in this case, and
    driving stopped at 39.
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient reported a history of night blindness (NB) and visual field constriction (VFC) since he was 30 years old, preceded by photophobia and episodes of photopsia already noted ten years before. Diagnosis of arRP was made when he was 32 years old and both NB and VFC became prominent at 35, when light aversion also developed. The patient could no longer drive by the age of 39."
    explanation: >-
      The staged natural history for this phase, including age at diagnosis.
- phase: Advanced retinal degeneration with retained residual vision
  age_range: 49 to 63 years
  notes: >-
    Acuity reaches 20/200 with fields under 10 degrees by 49, yet useful
    residual vision persists into the seventh decade. The slow tail matters
    clinically: it is the window any future therapy would have to act in.
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When he was 49 years old, visual acuity was 20/200 in both eyes with a fundus characterized by attenuated vessels, rare bone spicule-like deposits scattered in mid-periphery and prominent patches of 360° chorioretinal nummular atrophy in far periphery."
    explanation: >-
      Establishes the level of impairment at 49.
diagnosis:
- name: Ophthalmic phenotyping with next-generation sequencing
  description: >-
    Retinal phenotyping (electroretinography, full-field stimulus threshold,
    multimodal imaging) establishes the dystrophy; sequencing establishes the
    gene. The extra-ocular features are what should prompt looking at ARL2BP
    specifically rather than a generic RP panel result: a patient with RP plus
    situs inversus is a very short differential.
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy."
    explanation: >-
      Names the phenotyping modalities that establish the retinal diagnosis.
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4."
    explanation: >-
      The molecular confirmation step, in a real diagnostic sequence.
differential_diagnoses:
- name: Senior-Loken, Bardet-Biedl and Joubert syndromes
  description: >-
    All are ciliopathies combining retinal dystrophy with renal disease, and
    the renal cysts reported in one ARL2BP patient put them directly in the
    frame. The authors who reported that patient say so explicitly.
  evidence:
  - reference: PMID:38649918
    reference_title: "A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases."
    explanation: >-
      Names this differential and its trigger.
- name: Primary ciliary dyskinesia
  description: >-
    Shares situs inversus and male infertility from motile ciliary dysfunction.
    Retinal degeneration is not a feature of PCD, so the retinal arm separates
    them.
- name: Non-syndromic autosomal recessive retinitis pigmentosa
  description: >-
    RP66 will look non-syndromic in any patient without situs inversus, which
    is roughly what "with or without situs inversus" means. Separating them
    requires asking about laterality, fertility and renal anatomy, none of
    which an ophthalmic workup covers.
discussions:
- discussion_id: rp66_absence_of_disease_modifying_therapy
  kind: KNOWLEDGE_GAP
  attaches_to:
  - treatments#
  prompt: >-
    Is there any therapy that alters the course of ARL2BP-related retinal
    degeneration, and what should be curated when the honest answer is no?
  rationale: >-
    This entry has an empty `treatments:` section, and that is a finding rather
    than an omission. No therapy has been shown to modify the course of
    retinitis pigmentosa of any genotype, so there is nothing RP66-specific to
    curate; the best available statement is a Cochrane review's, and it is
    about RP as a class rather than about this gene. What patients receive is
    supportive care, which is not documented for RP66 anywhere in the cited
    literature. Curating it from general practice would manufacture
    disease-specific claims. If a heritable-retinal-dystrophy management
    guideline is added to the KB later, the supportive measures can be curated
    against it at `directness: INDIRECT`.
  evidence:
  - reference: PMID:32573764
    reference_title: "Vitamin A and fish oils for preventing the progression of retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "At this time, there is no proven therapy for RP."
    explanation: >-
      A Cochrane review's summary of the therapeutic landscape. Graded INDIRECT
      because it is a statement about retinitis pigmentosa as a class, not
      about the ARL2BP subtype this entry describes.
- discussion_id: rp66_incomplete_penetrance_of_the_motile_cilia_arm
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Motile Cilia and Flagellar Dysfunction
  - phenotypes#Situs inversus totalis
  prompt: >-
    Why is the retinal arm obligate while the motile-cilia arm is variable, if
    both follow from the same axonemal defect?
  rationale: >-
    Every reported ARL2BP patient has retinal degeneration; only some have
    situs inversus, and the disease name records that. If one protein is
    required for both primary and motile ciliary axonemes, the difference needs
    an explanation. Candidates include allele severity, the stochastic nature
    of nodal flow (where partial function gives randomised rather than reversed
    situs, so half of affected embryos would look normal), and redundancy in
    motile-cilia axoneme assembly that photoreceptors lack. None has been
    tested: no ARL2BP genotype-laterality correlation has been reported, and
    situs has not been scored in the knockout mouse in the source used here.
    The entry therefore models one shared upstream node branching into two
    arms, without asserting a reason for the asymmetry.
  proposed_experiments:
  - experiment_id: rp66_nodal_cilia_in_arl2bp_ko
    name: Nodal ciliary motility and laterality scoring in Arl2bp knockout embryos
    description: >-
      Score situs and nodal ciliary beat in a cohort of Arl2bp knockout
      embryos, to test whether laterality is randomised (stochastic nodal
      failure) or consistently reversed.
    readouts:
    - name: Proportion of embryos with reversed situs
      target: pathophysiology#Motile Cilia and Flagellar Dysfunction
      direction: ALTERED
      interpretation: >-
        Approximately half reversed would support stochastic nodal failure and
        explain the human variability without invoking allele severity.
- discussion_id: rp66_phenotype_expanding_one_case_at_a_time
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Unilateral renal agenesis
  - phenotypes#Renal cyst
  - phenotypes#Anosmia
  prompt: >-
    Are the renal, olfactory and cryptorchidism findings features of RP66, or
    coincidences in consanguineous pedigrees?
  rationale: >-
    Renal agenesis, renal microcysts, cryptorchidism and anosmia each rest on a
    single patient, and every reported family is consanguineous, which is
    exactly the setting in which a second recessive condition can segregate
    unnoticed. The reporting authors are appropriately careful, describing
    these as expanding the manifestations rather than as established features,
    and one writes only that the patient "likely had olfactory dysfunction
    susceptibility". They are curated because a ciliopathy mechanism makes them
    plausible and because omitting them would hide real observations, but each
    is a single case and the entry does not assert a frequency for any of them.
notes: >-
  On the deep-research report. An openscientist report was generated and used
  as leads. `just preflight-dr` returned WARN on two counts, both of which
  changed what was curated.

  First, ARL2 is mentioned 19 times against 61 for ARL2BP. Much of the
  ARL2/ARL3 photoreceptor-trafficking literature the report draws on concerns a
  different disease: PMID:25422369, which the report cites, is about RP2 and
  X-linked retinitis pigmentosa 2, not this disorder. It is not cited here and
  not committed.

  Second, the report gives `HGNC:702` as the ARL2BP identifier. That is wrong:
  the correct one is `hgnc:17146`, which is what this entry binds. The report's
  own Term Validation section did not flag it, so it was caught by checking the
  CURIE rather than by trusting the report.

  A correction to an earlier version of this note. It previously claimed the
  report confused the ARL2BP gene MIM (615407) with the RP66 phenotype MIM
  (615434), and gave that as the reason for carrying no OMIM assertion. That
  was wrong, and review caught it: the report distinguishes the two correctly
  in three places, including its header line and a table with separate
  "OMIM (phenotype)" 615434 and "OMIM (gene)" 615407 rows. The entry now
  carries the phenotype MIM as an `external_assertions` record, cited to
  PMID:38649918 rather than to the report, because that paper states both
  identifiers with their roles in a single sentence.

  Every PMID used from the report was verified against PubMed before citation.

  On two source typographies reproduced rather than corrected. PMID:23849777
  writes "ARLBP2" for ARL2BP in the abstract sentence quoted on the
  loss-of-function node. Snippets are exact quotes, so it stands, and the
  explanation says so.

  Not curated, and why. No `treatments:` - no proven disease-modifying therapy
  exists for retinitis pigmentosa of any genotype, and the supportive measures
  the report lists (low-vision rehabilitation, assisted reproduction) are
  generic to retinal dystrophy and male infertility rather than evidenced for
  RP66. That absence is recorded as a KNOWLEDGE_GAP discussion attached to
  `treatments#`, carrying the Cochrane review's statement at
  `directness: INDIRECT`, rather than left as an uncited sentence in
  `description`. No `datasets:` or `clinical_trials:` - no verified accession or
  registration. No `environmental:` - no exposure implicated. `directness` is
  set on four items only, where it was actually assessed.
📚

References & Deep Research

References

4
PMID:23849777
Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa.
No top-level findings curated for this source.
PMID:29718757
ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure.
No top-level findings curated for this source.
PMID:36507858
Novel homozygous variant in ARL2BP associated with retinitis pigmentosa, situs inversus, and male infertility in a Chinese patient.
No top-level findings curated for this source.
PMID:38649918
A novel homozygous splice site variant in ARL2BP causes a syndromic autosomal recessive rod-cone dystrophy with situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts.
No top-level findings curated for this source.

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

On the deep-research report. An openscientist report was generated and used as leads. `just preflight-dr` returned WARN on two counts, both of which changed what was curated. First, ARL2 is mentioned 19 times against 61 for ARL2BP. Much of the ARL2/ARL3 photoreceptor-trafficking literature the report draws on concerns a different disease: PMID:25422369, which the report cites, is about RP2 and X-linked retinitis pigmentosa 2, not this disorder. It is not cited here and not committed. Second, the report gives `HGNC:702` as the ARL2BP identifier. That is wrong: the correct one is `hgnc:17146`, which is what this entry binds. The report's own Term Validation section did not flag it, so it was caught by checking the CURIE rather than by trusting the report. A correction to an earlier version of this note. It previously claimed the report confused the ARL2BP gene MIM (615407) with the RP66 phenotype MIM (615434), and gave that as the reason for carrying no OMIM assertion. That was wrong, and review caught it: the report distinguishes the two correctly in three places, including its header line and a table with separate "OMIM (phenotype)" 615434 and "OMIM (gene)" 615407 rows. The entry now carries the phenotype MIM as an `external_assertions` record, cited to PMID:38649918 rather than to the report, because that paper states both identifiers with their roles in a single sentence. Every PMID used from the report was verified against PubMed before citation. On two source typographies reproduced rather than corrected. PMID:23849777 writes "ARLBP2" for ARL2BP in the abstract sentence quoted on the loss-of-function node. Snippets are exact quotes, so it stands, and the explanation says so. Not curated, and why. No `treatments:` - no proven disease-modifying therapy exists for retinitis pigmentosa of any genotype, and the supportive measures the report lists (low-vision rehabilitation, assisted reproduction) are generic to retinal dystrophy and male infertility rather than evidenced for RP66. That absence is recorded as a KNOWLEDGE_GAP discussion attached to `treatments#`, carrying the Cochrane review's statement at `directness: INDIRECT`, rather than left as an uncited sentence in `description`. No `datasets:` or `clinical_trials:` - no verified accession or registration. No `environmental:` - no exposure implicated. `directness` is set on four items only, where it was actually assessed.

Review round 1: address REQUEST_CHANGES on PR #11266 · 2026-09-07T10:43:17Z · View source

Addressed all three blocking items from the automated review plus every optional suggestion. IMPORTANT 1: added HP:0001133 Constriction of peripheral visual field and HP:0007737 Spicular pigmentation of the retina, both quoted from the full text of PMID:38649918 already committed in this PR. IMPORTANT 2: added five variants to genetic.variants (c.101-1G>C; c.134T>G p.Met45Arg; c.22_23delAG p.S8Lfs*10; c.294-1G>C; and c.100+1G>T, which was found by following the reviewer's prevalence lead and is absent from the deep-research report's variant table), each with a verified quote from a cached source, and added penetrance COMPLETE with expressivity VARIABLE to the inheritance record, evidenced by two biallelic sisters who had no situs inversus. IMPORTANT 3: the reviewer was correct that the notes misrepresented the deep-research report, which does distinguish gene MIM 615407 from phenotype MIM 615434 in three places; the note is corrected and an external_assertions record carries OMIM:615434 cited to PMID:38649918 rather than to the report. Suggestions taken: a three-phase progression section from the long-followed case; the prevalence evidence replaced, having quoted a variant report rather than an occurrence measure, with the 1 in 72 cohort figure from PMID:40384762; the absent treatments section recorded as a KNOWLEDGE_GAP discussion attached to treatments# carrying the Cochrane statement at directness INDIRECT, with the description softened to match; motile-cilia node biological_scale changed from ORGANISM to CELLULAR; CL:0000573 retinal cone cell added. Two reference caches added (PMID:32573764, PMID:40384762). Two self-inflicted defects were caught and fixed during the round: a reference title written from memory rather than from the cache, caught by the reference validator; and a scripted replacement that silently deleted the disease_term, synonyms, parents, references and inheritance sections, which every gate accepted because all five slots are optional and which was caught only by a structural diff against HEAD. All sections were restored and a structural comparison confirms nothing lost or shrunk. Validated: just validate-disorders (55/55 snippets verified), validate-terms, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-qualifier-terms, check-qualifier-terms-online.

Create: Retinitis Pigmentosa With or Without Situs Inversus · 2026-09-06T19:51:38Z · View source

De novo curation of RP66 / ARL2BP-related rod-cone dystrophy (MONDO:0014186). An openscientist deep-research report was generated and used as leads; preflight returned WARN on two counts that both changed the curation. ARL2 is mentioned 19 times against 61 for ARL2BP and the report cites PMID:25422369, which is about RP2 and X-linked RP2 rather than this disease; it is not cited here. The report also gives OMIM 615407, the ARL2BP gene MIM, where MONDO xrefs the RP66 phenotype MIM 615434, so no OMIM external_assertion is recorded. Six pathophysiology nodes branch one ciliary axoneme defect into an obligate retinal arm and a variable motile-cilia arm (situs inversus, sperm, olfactory), with a KNOWLEDGE_GAP on why the retinal arm is obligate and the other is not. Arl2bp knockout mouse and patient fibroblasts are both linked via modeled_mechanisms with scale and limitations. Validated: just validate (38/38 snippets verified), validate-terms, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys all pass.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 13 citations 2026-09-06T19:42:46.187673

1. Disease Information

Retinitis Pigmentosa With or Without Situs Inversus is a Mendelian inherited retinal dystrophy in which progressive rod–cone degeneration (retinitis pigmentosa) occurs either in isolation or accompanied by laterality defects (situs inversus) and other ciliopathy features. It is a primary retinal ciliopathy — the underlying lesion affects the photoreceptor connecting cilium, a specialized primary cilium.

Key identifiers:

Resource Identifier
MONDO MONDO:0014186
OMIM (phenotype) #615434 (Retinitis pigmentosa 66; RP66/RP with or without situs inversus)
OMIM (gene) 615407 (ARL2BP)
Gene / HGNC ARL2BP / HGNC:702
NCBI Gene GeneID 23568
UniProt Q9Y2Y0
Ensembl ENSG00000102931
Cytogenetic location 16q13 (GRCh38 chr16:57,245,259–57,253,635)

Synonyms / alternative names: Retinitis pigmentosa 66 (RP66); RP with situs inversus; ARL2BP-related retinitis pigmentosa; ARL2BP-related syndromic rod–cone dystrophy. Gene aliases: BART, BART1, RP66, RP82.

Information source type: The knowledge base entry is derived primarily from aggregated disease-level resources (OMIM, ClinVar, gnomAD, UniProt, NCBI Gene) supplemented by individual patient case reports describing single families or probands. It is not derived from large EHR cohorts, reflecting the disease's rarity.

2. Etiology

Primary cause — genetic. The disease is monogenic and Mendelian: biallelic (homozygous or compound-heterozygous) loss-of-function variants in ARL2BP cause the phenotype. There is no environmental, infectious, or acquired etiology. The original identification used a combination of homozygosity mapping and exome sequencing in two consanguineous families to establish ARL2BP as causative (PMID: 23849777): "we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66)."

Genetic risk factors. The causal alleles are the pathogenic ARL2BP variants themselves (see Section 4). Because the disorder is recessive, consanguinity is the dominant risk-elevating factor — all originally reported families were consanguineous with homozygous variants. No modifier loci or susceptibility SNPs have been established for this ultra-rare disorder.

Environmental risk factors. None identified or expected for a monogenic recessive disorder. General retinitis-pigmentosa risk modifiers such as light exposure are not established for the ARL2BP subtype.

Protective factors. No genetic or environmental protective factors have been identified. Population constraint data (gnomAD: pLI ≈ 5.8×10⁻⁶, observed/expected LoF ≈ 0.79) indicate ARL2BP is tolerant of heterozygous loss of function — consistent with carriers being unaffected and disease requiring biallelic loss.

Gene–environment interactions. None documented. Disease expression is determined by genotype; the "with or without situs inversus" variability reflects the stochastic nature of left–right axis determination by motile nodal cilia rather than any environmental interaction.

3. Phenotypes

The phenotype is a syndromic rod–cone dystrophy with variable extra-ocular ciliopathy features. Core and associated phenotypes, with suggested HPO terms:

Phenotype Type HPO term (suggested) Onset Severity / progression Frequency
Retinitis pigmentosa / rod–cone dystrophy Clinical sign HP:0000510 (Rod-cone dystrophy) Photophobia ~20 y; nyctalopia & central vision loss ~30 y Progressive; can be slow Constant (100%)
Night blindness (nyctalopia) Symptom HP:0000662 Early Progressive Very frequent
Photophobia Symptom HP:0000613 Often first symptom (~20 y) Progressive Frequent
Constricted / peripheral visual field loss Clinical sign HP:0001133 Early–mid adult Progressive Very frequent
Bone-spicule retinal pigmentation Physical manifestation HP:0007737 Adult Progressive Typical
Reduced/absent ERG responses Laboratory/functional HP:0000512 (Abnormal ERG) Early Progressive Constant
Situs inversus totalis Physical manifestation HP:0001696 Congenital Stable ~50% ("with or without")
Male infertility (oligo-/asthenozoospermia) Laboratory / clinical HP:0000798 / HP:0012041 Post-pubertal Stable Reported subset of males
Unilateral renal agenesis Physical manifestation HP:0000122 Congenital Stable Rare
Renal microcysts Physical manifestation HP:0000107 (Renal cyst) Variable Variable Rare
Cryptorchidism Physical manifestation HP:0000028 Congenital Stable Rare
Anosmia / olfactory dysfunction Symptom HP:0000458 Variable Stable Rare

The multisystem triad of RP, situs inversus, and male infertility was explicitly described as novel in a Chinese patient (PMID: 36507858): "presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia … this a novel ARL2BP-associated phenotypic triad of RP, situs inversus, and male infertility." Renal and sperm involvement was further documented (PMID: 38649918): "a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts."

Quality-of-life impact. The dominant burden is progressive vision loss, which impairs mobility, reading, driving, and independence and is a leading cause of visual disability; situs inversus totalis is generally asymptomatic; male infertility affects family planning. No disease-specific QoL instrument data exist for this ultra-rare subtype, but generic RP QoL measures (VFQ-25, low-vision instruments) apply.

Progression note. Course can be relatively slow — one patient retained useful residual vision at age 63 with slow progression over 5 years of follow-up (PMID: 38649918).

4. Genetic / Molecular Information

Causal gene: ARL2BP (GeneID 23568; OMIM 615407; HGNC:702; UniProt Q9Y2Y0), 16q13. NCBI summary: "This protein is considered to be the first ARL2-specific effector identified, due to its interaction with ARL2.GTP but lack of ARL2 GTPase-activating protein activity."

Pathogenic variants (all germline; no somatic involvement):

Variant (cDNA) Protein / effect Type Classification Source
c.101-1G>C Alters pre-mRNA splicing (splice acceptor) Splice-site Pathogenic PMID: 23849777
c.134T>G p.Met45Arg — reduces ARL2 binding, abolishes basal-body localization Missense Pathogenic PMID: 23849777
c.22_23delAG p.Ser8Leufs*10 Frameshift (null) Pathogenic PMID: 36507858
c.294-1G>C Splice acceptor Splice-site Pathogenic PMID: 38649918

Variant classification (ACMG/AMP): ClinVar (accessed 2026) holds 146 ARL2BP variant records: ~11 Pathogenic and ~2 Likely pathogenic (predominantly splice-site and frameshift null alleles), ~10 VUS, ~8 likely-benign, and 1 with conflicting classifications. The predominance of null/loss-of-function pathogenic alleles supports a loss-of-function disease mechanism.

Allele frequency: Pathogenic alleles are extremely rare/absent in gnomAD, consistent with a recessive disorder confined to consanguineous or founder contexts. ARL2BP is LoF-tolerant in heterozygotes (pLI ≈ 5.8×10⁻⁶; o/e LoF ≈ 0.79).

Functional consequence: Loss of function. The p.Met45Arg missense allele mechanistically reduces ARL2 binding and abolishes ARL2BP localization to the photoreceptor basal body — a demonstrated pathomechanism rather than merely predicted (PMID: 23849777).

Modifier genes: None established. Epigenetic changes: Not implicated. Chromosomal abnormalities: None; the disease is caused by point/small variants, not large structural rearrangements (situs inversus here is a ciliary-motility consequence, not a chromosomal inversion despite the name).

5. Environmental Information

There are no environmental, lifestyle, or infectious contributors to this monogenic recessive disorder. No toxins, radiation, occupational exposures, dietary factors, or pathogens are implicated in causing or triggering ARL2BP-related disease. The only relevant "environmental" factor in a population-genetics sense is consanguineous mating, which increases the probability of homozygosity for rare recessive alleles.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function mutation in ARL2BP (splice, frameshift, or function-abolishing missense) → loss or dysfunction of ARL2BP protein.
  2. Loss of ARL2BP → failure to anchor/localize at the ciliary basal body and cilium-associated centriole of photoreceptors (demonstrated: p.Met45Arg abolishes basal-body localization; ARL2 depletion displaces ARL2BP) (PMID: 23849777).
  3. Mislocalized/absent ARL2BP → disrupted ARL2/ARL3 small-GTPase cycle (ARL2BP is the first ARL2-GTP-specific effector and acts as a co-GEF stabilizing active ARL3-GTP) (PMID: 33438581).
  4. Impaired ARL3 activity → defective ciliary trafficking of lipid-modified (prenylated/myristoylated) phototransduction proteins via the RP2–ARL3–PDE6D axis, which chaperones prenylated cargo such as PDE6 and GRK1 into the outer segment (PMID: 25422369).
  5. Branch A (sensory cilium / retina): cargo mistrafficking + axonemal defect → disorganized photoreceptor outer segments with vertically aligned disks, shortened axonemes, open B-tubule doublets, and loss of singlet microtubules (demonstrated in KO mouse) (PMID: 29718757) → progressive rod and cone death → retinitis pigmentosa (nyctalopia → field loss → central vision loss).
  6. Branch B (motile cilia): the same ciliary/axonemal assembly defect in embryonic nodal cilia → randomized left–right axis determination → situs inversus (present in ~half of patients); in sperm flagella → oligo-/asthenozoospermia → male infertility; in airway cilia → potential primary-ciliary-dyskinesia-type respiratory features; in renal cilia → renal agenesis/microcysts; in olfactory cilia → anosmia.

Detail by category

  • Molecular pathways: ARL2/ARL3 GTPase signaling; RP2–ARL3–PDE6D lipidated-cargo ciliary trafficking. ARL2BP moonlights in ARL2-dependent STAT3 nuclear translocation/transcriptional activity (UniProt Q9Y2Y0: "Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3.").
  • Cellular processes: Ciliogenesis and ciliary maintenance; intraflagellar/ciliary protein transport; photoreceptor outer-segment disk morphogenesis; progressive photoreceptor apoptosis.
  • Protein dysfunction: Loss of function via truncation (frameshift/splice) or loss of ARL2 binding + mislocalization (p.Met45Arg). GO molecular functions: GTPase regulator activity (GO:0030695), transcription coactivator activity (GO:0003713).
  • Metabolic changes: Disrupted delivery of PDE6 (cGMP phototransduction cascade) impairs the visual cycle at the outer segment; broader metabolic changes not characterized.
  • Immune involvement: None; not an autoimmune/inflammatory disease.
  • Tissue damage mechanism: Structural failure of the connecting cilium/axoneme leading to outer-segment malformation and photoreceptor degeneration.
  • Biochemical abnormalities: Failure of the ARL2BP→ARL3-GTP→PDE6D trafficking module; mislocalization of prenylated phototransduction enzymes.

Suggested GO / CL terms: BP — cilium assembly (GO:0060271), intraciliary transport (GO:0042073), photoreceptor cell maintenance (GO:0045494), determination of left/right symmetry (GO:0007368), regulation of GTPase activity (GO:0043087). CC — ciliary basal body (GO:0036064), photoreceptor connecting cilium (GO:0032391), centrosome (GO:0005813). CL — retinal rod cell (CL:0000604), retinal cone cell (CL:0000573), ciliated cell (CL:0000064), sperm (CL:0000019).

7. Anatomical Structures Affected

Organ level (primary): Eye — retina, specifically the photoreceptor layer (UBERON:0000970 eye; UBERON:0000966 retina; UBERON:0001789 photoreceptor layer). Secondary/associated organs: thoraco-abdominal viscera (laterality reversal in situs inversus — heart, lungs, liver, spleen, stomach mirror-imaged), testis/sperm (male reproductive system), kidney, olfactory epithelium.

Body systems involved: visual/nervous (sensory), reproductive (male infertility), renal/urinary, respiratory (if PCD features), and the visceral situs of cardiovascular/digestive systems.

Tissue and cell level: Neural retina — rod photoreceptors (CL:0000604) and cone photoreceptors (CL:0000573) are the primary targets; motile ciliated cells of node, airway, and reproductive tract; renal tubular epithelium. Patient fibroblasts (in vitro) show shortened cilia and reduced proliferation (PMID: 36507858).

Subcellular level: The connecting cilium / basal body (GO:0036064) is the central compartment. UniProt/GO also annotate ARL2BP to centrosome (GO:0005813), spindle (GO:0005819), midbody (GO:0030496), cytosol (GO:0005829), nucleoplasm (GO:0005654), and mitochondrial intermembrane space (GO:0005758)/matrix (GO:0005759) — reflecting moonlighting roles.

Localization / lateralization: Retinal involvement is bilateral and roughly symmetric; situs inversus is a whole-body laterality reversal (mirror-image organ arrangement); renal agenesis reported as unilateral.

8. Temporal Development

Onset: Situs inversus and renal/laterality anomalies are congenital. Retinal disease is typically young-adult onset: photophobia often first at ~20 years, nyctalopia and central vision loss by ~30 years (PMID: 38649918). Onset pattern is insidious and chronic.

Progression: Chronic, lifelong, and progressive but can be slow — one patient retained useful residual vision at 63 with slow progression over a 5-year window (PMID: 38649918). Typical RP staging applies: early (night blindness, mid-peripheral field loss) → intermediate (ring scotoma, constricted fields) → advanced (tunnel vision) → end-stage (central/legal blindness). Situs inversus is stable and non-progressive.

Patterns: No remissions; no relapsing–remitting course. The therapeutic window for any future retinal gene therapy is early disease while viable photoreceptors remain — an important critical-period consideration.

9. Inheritance and Population

Inheritance: Autosomal recessive. Biallelic ARL2BP variants; reported families are consanguineous with homozygous alleles.

Penetrance / expressivity: Retinal disease appears fully penetrant in biallelic carriers; situs inversus shows incomplete penetrance / variable expressivity ("with or without"), reflecting the stochastic left–right axis determination by nodal cilia. Extra-ocular features (renal, olfactory, fertility) are variably expressed.

Founder effects / consanguinity: Strong consanguinity contribution; homozygous variants in geographically distinct families (Middle East, China, Italy, Pakistan). No genetic anticipation, germline mosaicism, or repeat-expansion mechanism.

Epidemiology: Retinitis pigmentosa overall has a worldwide prevalence of ~1:4,000 (~100,000 affected in the USA), with 20–30% of cases syndromic (PMID: 29597005): "RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20-30% of patients with RP also have an associated non-ocular condition." ARL2BP-related RP (RP66) is an ultra-rare subtype — only a handful of families reported worldwide. In a consanguineous Pakistani IRD cohort it accounted for 1 of 72 families (1.4%) (PMID: 40384762): "…1/72(1.38%) … in … retinitis pigmentosa with situs inversus … segregated families."

Sex ratio: Retinal disease affects both sexes; the infertility phenotype is specific to males. Carrier frequency: Not precisely established; expected very low outside consanguineous populations.

10. Diagnostics

Ophthalmic evaluation (core): Full-field electroretinogram (ERG) shows markedly reduced or absent rod and cone responses; fundus shows bone-spicule pigmentation and optic-disc pallor; OCT and fundus autofluorescence (FAF) show progressive loss of outer retinal layers (PMID: 29597005): "Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers." ARL2BP cases were additionally assessed with full-field stimulus threshold testing and multimodal imaging (PMID: 38649918).

Molecular genetic testing (definitive): Next-generation sequencing — targeted IRD capture panels (e.g., a 344-gene panel, PMID: 40384762), whole-exome, or whole-genome sequencing — with ACMG/AMP variant interpretation and Sanger segregation confirmation. Homozygosity mapping is valuable in consanguineous families (PMID: 23849777).

Extra-ocular workup: Chest X-ray/abdominal imaging/echocardiography to detect situs inversus; semen analysis for oligo-/asthenozoospermia; renal ultrasound for agenesis/microcysts; olfactory testing where indicated.

Differential diagnosis: Other syndromic retinal ciliopathies — Usher syndrome, Bardet–Biedl syndrome, Senior–Løken syndrome, and other RP-with-situs-inversus/PCD overlaps; distinguished by gene panel and by the specific extra-ocular pattern. Screening: Cascade genetic testing of at-risk relatives and carrier testing in consanguineous families once the familial variant is known.

11. Outcome / Prognosis

Survival / mortality: The disorder is not life-limiting in itself. Situs inversus totalis is typically asymptomatic and compatible with normal lifespan. Life expectancy is generally normal unless significant primary-ciliary-dyskinesia respiratory disease is present.

Morbidity / function: The principal morbidity is progressive, irreversible vision loss leading to legal blindness in advanced disease — a major disability outcome with substantial QoL impact. Male infertility is a reproductive-health morbidity. Recovery potential: None with current therapy; photoreceptor loss is irreversible.

Disease course / complications: Chronic, progressive vision loss; cystoid macular edema and cataract can complicate RP generally; PCD-associated respiratory infections if motile-cilia airway disease is present.

Prognostic factors: Age at onset, rate of ERG/field decline, and residual outer-retinal structure on OCT predict visual outcome. Some ARL2BP patients show relatively slow progression with preserved vision into the seventh decade (PMID: 38649918).

12. Treatment

There is no proven disease-modifying therapy. A 2020 Cochrane review of vitamin A and DHA/fish oils concluded evidence for slowing RP progression is limited/uncertain (PMID: 32573764): "At this time, there is no proven therapy for RP."

Supportive / rehabilitative care (mainstay): Visual aids, orientation and mobility training, and nutritional supplementation provide only symptomatic relief and do not halt progression (PMID: 40731809): "While current management is largely supportive-relying on visual aids, orientation training, and nutritional supplementation-these interventions offer only symptomatic relief and do not halt disease progression." (NCIT: Supportive Care; Low Vision Aid.)

Not applicable: The only approved retinal gene therapy, voretigene neparvovec (Luxturna), is specific to biallelic RPE65 mutations and does not apply to ARL2BP (PMID: 37762059).

Investigational: AAV gene-replacement, RNA-based, and CRISPR/Cas9 strategies are advancing for RP broadly but remain investigational for ARL2BP (PMID: 40869487, PMID: 40731809). ARL2BP's small coding sequence makes it a favorable candidate for AAV gene replacement in principle.

Management of extra-ocular features: Situs inversus totalis usually needs no treatment; PCD-type respiratory disease (if present) needs airway clearance/antibiotics; male infertility may be addressed with assisted reproduction (ICSI). (NCIT: Assisted Reproductive Technology; Intracytoplasmic Sperm Injection.)

Pharmacogenomics / personalized medicine: No genotype-guided pharmacotherapy exists; future precision approaches would be gene-replacement or variant-specific (e.g., splice-modulating ASOs for splice-site alleles).

13. Prevention

Being monogenic and recessive, prevention is genetic/reproductive, not lifestyle-based.

  • Primary prevention: Not achievable by risk-factor modification. Genetic counseling for consanguineous families and known carriers; recurrence risk is 25% per pregnancy for two carrier parents.
  • Carrier / cascade screening: Test at-risk relatives once the familial ARL2BP variant is identified.
  • Reproductive options: Prenatal diagnosis and preimplantation genetic testing (PGT-M) for couples known to carry pathogenic ARL2BP variants.
  • Secondary/tertiary prevention: Early ophthalmic monitoring to manage complications (cataract, macular edema), low-vision rehabilitation, and airway surveillance where PCD features exist. No immunization or public-health intervention is relevant.

14. Other Species / Natural Disease

Orthologs (NCBI Gene): mouse Arl2bp (GeneID 107566), rat Arl2bp (GeneID 498910), zebrafish arl2bp (GeneID 393976). A functional ARL2BP homolog is present and essential in ciliate protozoa, where RNAi is lethal and disrupts cortical microtubules (PMID: 40432967): "RNAi of ARL2BP and DYNLRB2 increased mortality, reduced motility, and disrupted cortical microtubule organization" — demonstrating deep evolutionary conservation of ARL2BP's ciliary/microtubule role.

Natural disease in other species: No well-characterized naturally occurring ARL2BP disease is documented in companion animals or wildlife (OMIA entries not established for this specific gene–disease pair). Comparative biology: The conserved ciliary function across mammals, fish, and protozoa underpins the utility of cross-species models. Zoonotic potential: None (non-transmissible genetic disease).

15. Model Organisms

Primary model — Arl2bp-knockout mouse: A knockout mouse recapitulates key human features (PMID: 29718757): "we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa. The KO mice display an early and progressive reduction in visual response." Structurally: "we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes … ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs."

  • Phenotype recapitulation: High for the retinal phenotype — early, progressive ERG decline; disorganized outer segments; connecting-cilium/axoneme and doublet-microtubule defects.
  • Applications: Studying outer-segment morphogenesis, ciliary microtubule assembly, ARL2/ARL3 trafficking, and as a preclinical platform for gene-replacement testing.
  • Limitations: Mouse retinal architecture (rod-dominant, no macula) limits translation of central-vision outcomes; extent to which the model reproduces situs inversus/laterality and fertility phenotypes is less fully characterized.

In vitro models: Patient-derived fibroblasts show reduced proliferation and shortened cilia (PMID: 36507858), providing a cellular ciliogenesis assay. Zebrafish and ciliate systems offer additional conserved platforms for ciliary-function studies.

Mechanistic Model / Interpretation

 ARL2BP biallelic LoF mutation (splice / frameshift / p.Met45Arg)
      │
      ▼
 Loss/dysfunction of ARL2BP protein
      │
      ▼
 Failure to localize at basal body / cilium-associated centriole
   (p.Met45Arg abolishes basal-body localization; loses ARL2 binding)
      │
      ▼
 Disrupted ARL2 / ARL3 GTPase cycle  (ARL2BP = ARL2-GTP effector + ARL3 co-GEF)
      │
      ▼
 Defective ARL3–PDE6D ciliary trafficking of prenylated proteins (PDE6, GRK1)
   + defective axoneme / doublet-microtubule assembly
      │
┌─────┴───────────────────────────────┐
▼ (sensory cilium)                     ▼ (motile cilia)
 Disorganized photoreceptor outer segment   Nodal cilia → SITUS INVERSUS (~50%)
 (vertical disks, short axoneme,            Sperm flagella → male infertility
  open B-tubules, lost singlet MTs)         Airway cilia → PCD-type disease
│                                    Renal cilia → agenesis/microcysts
▼                                    Olfactory cilia → anosmia
 Progressive rod & cone death
│
▼
 RETINITIS PIGMENTOSA (nyctalopia → field loss → central vision loss)

Upstream vs downstream: The mutation and ARL2BP loss are upstream; the ARL2/ARL3 cycle and PDE6D trafficking are the central molecular node; outer-segment malformation and photoreceptor death are downstream retinal outcomes; laterality/fertility/renal/olfactory features are parallel downstream consequences in motile-cilia tissues. The "with or without situs inversus" naming captures the branch point: the same molecular lesion produces retinal disease in all patients but laterality defects only when nodal-cilia motility is sufficiently disrupted during embryogenesis.

Evidence Base

PMID Title (abbrev.) Supports
23849777 Mutations in ARL2BP cause AR retinitis pigmentosa Gene discovery; causal variants; situs inversus; ARL2-binding mechanism
29718757 ARL2BP needed for photoreceptor cilia doublets and OS structure KO mouse model; ciliary/axonemal defect
25422369 Mistrafficking of prenylated proteins causes RP2 ARL3–PDE6D lipidated-cargo trafficking pathway
33438581 ARL3 activation requires co-GEF BART ARL2BP/BART as ARL3 co-GEF stabilizing ARL3-GTP
36507858 Novel ARL2BP variant: RP, situs inversus, infertility Phenotypic triad; frameshift allele; fibroblast cilia defect
38649918 Splice variant: situs inversus, asthenozoospermia, renal Renal/sperm phenotype expansion; slow progression
29597005 Non-syndromic retinitis pigmentosa RP prevalence 1:4000; diagnostic modalities
40384762 Consanguineous Pakistani IRD panel study Rarity (1/72 families); panel-based diagnosis
32573764 Vitamin A/fish oils for RP (Cochrane) No proven therapy for RP
40731809 RP: genetic insights to therapeutics Supportive-only management; investigational gene therapy
37762059 Gene therapy in hereditary retinal dystrophies Luxturna is RPE65-specific, not ARL2BP
40869487 Genetic therapies for RP Investigational AAV/RNA/CRISPR landscape
40432967 Cilia-associated gene families (ciliate) Deep conservation; essential ciliary role

Evidence source types: Human clinical/genetic (23849777, 36507858, 38649918, 40384762, 29597005); model organism (29718757 mouse; 40432967 ciliate); in vitro (36507858 fibroblasts; 33438581 biochemistry; 25422369); systematic review/therapeutic (32573764, 40731809, 37762059, 40869487).

Limitations and Knowledge Gaps

  • Ultra-rare with small n. The entire literature rests on a handful of families/probands. Penetrance estimates (especially the ~50% figure for situs inversus) are approximate, and genotype–phenotype correlations are underpowered.
  • No formal epidemiology. No registry-based prevalence/incidence for the ARL2BP subtype; figures derive from overall RP prevalence and single-cohort proportions.
  • QoL and natural-history data are absent for this specific subtype; progression rate estimates come from isolated case follow-up.
  • Motile-cilia phenotype incompletely characterized. The mechanistic link between ARL2BP loss and nodal/sperm/airway ciliary dysfunction is inferred from ciliopathy biology and case observations more than direct experiment; airway/PCD burden is not systematically documented.
  • Modifier and epigenetic factors unexplored; explanation for variable situs inversus penetrance is mechanistic/stochastic rather than empirically mapped.
  • No therapy validated — gene replacement is promising in principle but untested in ARL2BP models.

Proposed Follow-up Experiments / Actions

  1. International case registry / GeneMatcher recruitment to aggregate ARL2BP patients, refine penetrance of situs inversus, fertility, renal and olfactory involvement, and establish natural-history/progression rates.
  2. AAV-ARL2BP gene-replacement proof-of-concept in the Arl2bp-KO mouse — the small coding sequence fits AAV capacity; measure ERG rescue and outer-segment/axoneme restoration.
  3. Splice-modulating ASO testing for recurrent splice-acceptor alleles (c.101-1G>C, c.294-1G>C) in patient fibroblasts/iPSC-derived retinal organoids.
  4. iPSC-derived retinal organoids and multiciliated-airway cultures from patients to model both sensory- and motile-cilia branches and to quantify trafficking of prenylated cargo (PDE6, GRK1).
  5. Systematic PCD/airway and fertility phenotyping across the cohort to define the motile-cilia disease burden and inform surveillance guidelines.
  6. Structural/biochemical dissection of the ARL2BP–ARL2/ARL3 co-GEF interface to enable variant-specific functional classification of VUS in ClinVar.

Report compiled from 9 confirmed findings and 21 reviewed papers across a 5-iteration autonomous investigation. Evidence types and PMIDs are indicated throughout; ontology term suggestions (HPO, GO, CL, UBERON, NCIT) are embedded per section.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 13
On topic 9
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:33438581 (4 mentions) - ARL3 activation requires the co-GEF BART and effector-mediated turnover.
  • shared terms: arl3

Weighed against this report's own most characteristic terms: arl2bp, situs, inversus, disease, retinal, loss, gene, photoreceptor, renal, patient, progressive, feature, phenotype, pigmentosa, retinitis, familie, arl2, arl3, consanguineous, infertility.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 38
Resolved 37
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 13
Terms named correctly 2
Terms named as a different term 9
Terms whose name is worth a second look 2

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:

  • MONDO:0014186 (2 mentions) - the report calls it "MONDO"; MONDO calls it retinitis pigmentosa with or without situs inversus
  • HP:0000662 (1 mention) - the report calls it "Symptom"; HP calls it Nyctalopia
  • HP:0000613 (1 mention) - the report calls it "Symptom"; HP calls it Photophobia
  • HP:0001133 (1 mention) - the report calls it "Clinical sign"; HP calls it Constriction of peripheral visual field
  • HP:0007737 (1 mention) - the report calls it "Physical manifestation"; HP calls it Spicular pigmentation of the retina
  • HP:0001696 (1 mention) - the report calls it "Physical manifestation"; HP calls it Situs inversus totalis
  • HP:0000122 (1 mention) - the report calls it "Physical manifestation"; HP calls it Unilateral renal agenesis
  • HP:0000028 (1 mention) - the report calls it "Physical manifestation"; HP calls it Cryptorchidism
  • HP:0000458 (1 mention) - the report calls it "Symptom"; HP calls it Anosmia

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000512 (1 mention) - the report calls it "Abnormal ERG"; HP calls it Abnormal electroretinogram, and lists "Abnormal ERG" among its other names
  • GO:0036064 (2 mentions) - the report calls it "connecting cilium / basal body"; GO calls it ciliary basal body, and lists "cilium basal body" among its other names