CERKL-Related Retinopathy

Mendelian MONDO:0800401 Pathograph 7 Show in embeddings browser Ophthalmological Disease Retinal Dystrophy Inherited retinal dystrophy

CERKL-related retinopathy is an autosomal recessive inherited retinal dystrophy caused by biallelic pathogenic variants in CERKL (ceramide kinase-like). CERKL shares sequence homology with the ceramide kinase (CERK) enzyme but has no demonstrated catalytic kinase activity toward ceramide or any other confirmed substrate; instead it protects photoreceptors from oxidative-stress-induced apoptosis and regulates mitochondrial dynamics and autophagy. Loss of CERKL function is historically also known as retinitis pigmentosa 26 (RP26), the original linkage-mapped designation, but the clinical spectrum is broader than classic rod-cone RP: it ranges from isolated macular disease to severe retina-wide involvement, with electroretinographic patterns that generally do not fit the classic rod-cone/cone-rod dichotomy. CERKL is an uncommon overall cause of autosomal recessive retinitis pigmentosa but is a significant contributor in several founder populations (Finnish, Yemenite Jewish, Spanish, and Tunisian).

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1
Mappings
1
Inheritance
6
Pathophys.
6
Phenotypes
7
Pathograph
1
Genes
2
Medical Actions
5
References
🔗

Mappings

MONDO
MONDO:0012024 retinitis pigmentosa 26 Not Yet Curated
skos:narrowMatch MONDO
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Disease requires biallelic (homozygous or compound heterozygous) loss-of-function CERKL variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:14681825 SUPPORT Human Clinical
"All of the patients from the RP26 family bear a homozygous mutation in exon 5, which generates a premature termination codon."
Original gene-discovery report identifying the founding homozygous nonsense mutation.
PMID:33322828 SUPPORT Human Clinical
"Three were homozygotes and three were compound heterozygotes"
Confirms both homozygous and compound-heterozygous biallelic genotypes cause disease across an ethnically diverse cohort.
⚙

Pathophysiology

6
CERKL Biallelic Loss-of-Function
Biallelic loss-of-function variants (nonsense, frameshift, splice, or damaging missense) eliminate or severely reduce functional CERKL protein. CERKL is structurally related to ceramide kinase but has no demonstrated catalytic activity toward ceramide or any other identified substrate, so disease variants act through simple loss of the protein's (non-catalytic) protective function rather than through a gain-of-function or dominant-negative mechanism.
Downstream
Loss of CERKL-Mediated Protection Against Oxidative Stress Loss of CERKL protein removes its protective effect against oxidative-stress-induced apoptosis in photoreceptors and other retinal cells.
Show evidence (2 references)
PMID:14681825 SUPPORT Human Clinical
"All of the patients from the RP26 family bear a homozygous mutation in exon 5, which generates a premature termination codon."
Identifies the founding premature-termination-codon variant causing complete loss of CERKL protein function.
PMID:33322828 SUPPORT Human Clinical
"As yet, no kinase activity is reported for CERKL and its function remains unclear"
Confirms CERKL has no demonstrated catalytic kinase activity despite its ceramide-kinase homology, so disease variants cause loss of an unconventional, non-catalytic protective function.
Loss of CERKL-Mediated Protection Against Oxidative Stress
Wild-type CERKL protects cultured cells from apoptosis induced by oxidative stress; the RP-causing truncated R257X mutant does not. Loss of this protective function is proposed to tilt photoreceptors -- cells with high metabolic demand and chronic light-driven oxidative burden -- toward apoptosis.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Mitochondrial Fragmentation and Bioenergetic Dysfunction Loss of CERKL's protective function against oxidative stress is accompanied by disruption of mitochondrial structure and energy metabolism.
Dysregulated Autophagy Loss of CERKL function is accompanied by increased autophagy, part of the same organelle-stress response as mitochondrial fragmentation.
Show evidence (1 reference)
PMID:19158957 SUPPORT In Vitro
"CERKL (but not the RP R257X mutant) exerts a protective role in cells against oxidative stress, consistent with RP mutations impairing the normal protein function in photoreceptors and thus tilting the balance toward apoptosis."
Directly demonstrates loss of oxidative-stress protection by an RP-causing truncating variant, contrasted with protective wild-type CERKL.
Mitochondrial Fragmentation and Bioenergetic Dysfunction
CERKL isoforms localize in part to mitochondria in retinal neurons. Depletion of CERKL in knockdown/knockout mouse retinas causes mitochondrial fragmentation, altered mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism, establishing CERKL as a regulator of mitochondrial dynamics in the retina.
mitochondrial fission GO:0000266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mitochondrial fission (GO:0000266). GO:0000266 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Combined Rod and Cone Photoreceptor Apoptosis Impaired mitochondrial bioenergetics compromises photoreceptor survival, contributing to apoptosis in both rods and cones.
Show evidence (1 reference)
PMID:34048907 SUPPORT Model Organism
"The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism."
Mouse retina model directly links CERKL loss to mitochondrial fragmentation and bioenergetic/metabolic dysfunction.
Dysregulated Autophagy
CERKL depletion increases autophagy in retinal neurons, part of a disrupted organelle-quality-control response accompanying mitochondrial fragmentation.
autophagy GO:0006914 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Combined Rod and Cone Photoreceptor Apoptosis Dysregulated autophagy compounds cellular stress, contributing to apoptosis in both rods and cones.
Show evidence (1 reference)
PMID:34048907 SUPPORT Model Organism
"The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism."
The same mouse retina model demonstrates increased autophagy alongside mitochondrial fragmentation upon CERKL loss.
Combined Rod and Cone Photoreceptor Apoptosis
Unlike classic rod-first retinitis pigmentosa, CERKL loss produces electroretinographic patterns of similar severity in rods and cones in over half of tested patients, with the remainder split between rod-cone, cone-rod, and macular-dystrophy patterns -- reflecting combined loss of oxidative-stress protection and mitochondrial/autophagy dysfunction acting on both photoreceptor types rather than a strictly rod-first degenerative sequence.
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. 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.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Macular and Peripheral Retinal Atrophy Progressive rod and cone loss produces the clinically observed macular and peripheral chorioretinal atrophy.
Show evidence (1 reference)
PMID:37331655 SUPPORT Human Clinical
"53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern."
Multicenter natural-history cohort directly documents the mixed rod/cone electrophysiological pattern that does not fit the classic rod-cone/cone-rod dichotomy.
Macular and Peripheral Retinal Atrophy
The most common retinal finding is well-demarcated macular atrophy, often with a small preserved central island, accompanied in many patients by peripheral chorioretinal atrophic patches and variable intraretinal pigment deposition.
Show evidence (2 references)
PMID:37331655 SUPPORT Human Clinical
"the most common retinal feature was well-demarcated areas of macular atrophy (57%)"
Establishes macular atrophy as the single most common retinal structural finding in the largest CERKL natural-history cohort.
PMID:33322828 SUPPORT Human Clinical
"peripheral areas of loss-of-signal consistent with the chorioretinal atrophic patches"
Documents peripheral chorioretinal atrophic patches accompanying central macular atrophy in an individual patient.
⬡

Pathograph

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

Phenotypes

6
Eye 4
Reduced visual acuity FREQUENT HP:0007663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced visual acuity (HP:0007663), qualified as course progressive. HP:0007663 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:37331655 SUPPORT Human Clinical
"The most frequent initial symptom was central vision loss (40%)"
Central vision loss is the most common initial presenting symptom, and longitudinal follow-up shows continued progressive acuity decline in most patients.
Macular atrophy FREQUENT HP:0007401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macular atrophy (HP:0007401). HP:0007401 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37331655 SUPPORT Human Clinical
"the most common retinal feature was well-demarcated areas of macular atrophy (57%)"
Well-demarcated macular atrophy is the single most common retinal structural finding in the largest natural-history cohort to date.
Abnormal electroretinogram VERY_FREQUENT 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:37331655 SUPPORT Human Clinical
"64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern."
Every electrophysiologically assessed patient showed an abnormal pattern, split across four distinct dysfunction patterns rather than a single classic RP pattern.
Nyctalopia FREQUENT 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:33322828 SUPPORT Human Clinical
"characterised by symptoms of nyctalopia, peripheral visual field loss with a clinical appearance of intraretinal bone spicule pigmentation, pale discs and attenuated vasculature"
Nyctalopia is documented as a presenting symptom in this multi-ethnic CERKL cohort, consistent with the RP-pattern subset of the phenotype spectrum.
Other 2
Spicular pigmentation of the retina FREQUENT 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 (1 reference)
PMID:33322828 SUPPORT Human Clinical
"Widespread intraretinal bone spicule pigmentation was noted primarily in the mid-periphery"
Documents intraretinal bone spicule pigmentation in an individual CERKL patient; variable across the cohort (two of six patients had no pigment deposition), consistent with FREQUENT rather than universal frequency.
Chorioretinal atrophy FREQUENT HP:0000533 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chorioretinal atrophy (HP:0000533). HP:0000533 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33322828 SUPPORT Human Clinical
"distinct nummular RPE depigmentation in the mid-periphery with chorioretinal atrophic patches temporally"
Documents peripheral chorioretinal atrophic patches in an individual CERKL patient, accompanying the central macular atrophy.
🧬

Genetic Associations

1
CERKL
Gene: CERKL hgnc:21699 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CERKL (hgnc:21699). hgnc:21699 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:33322828 SUPPORT Human Clinical
"In these reported populations, CERKL is a significant gene contributing to autosomal recessive RP; presumably due to a founder mutation effect."
Documents CERKL founder mutations as significant contributors to autosomal recessive RP in Finnish, Yemenite Jewish, Spanish, and Tunisian populations, contrasted with its rarity elsewhere.
💊

Medical Actions

2
Low Vision Rehabilitation
Action: low vision rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is low vision rehabilitation, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Supportive low-vision aids and rehabilitation; no approved disease-modifying or gene therapy currently exists for CERKL-related retinopathy, though its small (1599 bp) coding sequence and recessive inheritance make it a plausible future AAV gene-therapy target.
Show evidence (1 reference)
PMID:33322828 SUPPORT Human Clinical
"To date, there are no therapeutic strategies to correct or treat the retinal degeneration caused by mutations in CERKL."
Confirms no disease-modifying treatment currently exists.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling addressing autosomal recessive inheritance and recurrence risk.
📊

Prevalence

1
Multiple founder populations (Finnish, Yemenite Jewish, Spanish, Tunisian)
Unknown Rare
No single quantitative prevalence estimate is available; CERKL is described qualitatively as an uncommon overall cause of autosomal recessive retinitis pigmentosa but a significant cause of disease in specific founder populations.
Show evidence (1 reference)
PMID:33322828 SUPPORT Human Clinical
"CERKL mutations are an uncommon cause of arRP, but they are a significant cause of disease in populations with founder mutations"
States the qualitative prevalence picture: rare overall, significant in specific founder populations.
{ }

Source YAML

click to show 
name: CERKL-Related Retinopathy
creation_date: "2026-07-23T00:00:00Z"
category: Mendelian
description: >
  CERKL-related retinopathy is an autosomal recessive inherited retinal
  dystrophy caused by biallelic pathogenic variants in CERKL (ceramide
  kinase-like). CERKL shares sequence homology with the ceramide kinase (CERK)
  enzyme but has no demonstrated catalytic kinase activity toward ceramide or
  any other confirmed substrate; instead it protects photoreceptors from
  oxidative-stress-induced apoptosis and regulates mitochondrial dynamics and
  autophagy. Loss of CERKL function is historically also known as retinitis
  pigmentosa 26 (RP26), the original linkage-mapped designation, but the
  clinical spectrum is broader than classic rod-cone RP: it ranges from
  isolated macular disease to severe retina-wide involvement, with
  electroretinographic patterns that generally do not fit the classic
  rod-cone/cone-rod dichotomy. CERKL is an uncommon overall cause of
  autosomal recessive retinitis pigmentosa but is a significant contributor
  in several founder populations (Finnish, Yemenite Jewish, Spanish, and
  Tunisian).
disease_term:
  preferred_term: CERKL-related retinopathy
  term:
    id: MONDO:0800401
    label: CERKL-related retinopathy
synonyms:
- CERKL retinitis pigmentosa
- Retinitis pigmentosa 26
- RP26
- CERKL-associated retinal dystrophy
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012024
      label: retinitis pigmentosa 26
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
notes: >-
  MONDO:0012024 (RP26) is the original, gene-linkage-era name for CERKL disease
  and is narrower than the umbrella CERKL-related retinopathy term: RP26 names
  only the classic rod-cone-pattern presentation, while the umbrella term also
  covers the macular-dystrophy and cone-rod-pattern presentations documented in
  the largest natural-history cohort to date. No separate MONDO identifiers
  exist for the cone-rod or macular-dystrophy presentations, so this entry
  models the full phenotype spectrum under the single umbrella term rather than
  forcing has_subtypes partitions the literature itself says do not cleanly
  separate.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Disease requires biallelic (homozygous or compound heterozygous)
    loss-of-function CERKL variants.
  evidence:
  - reference: PMID:14681825
    reference_title: "Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients from the RP26 family bear a homozygous mutation in exon 5, which generates a premature termination codon."
    explanation: >
      Original gene-discovery report identifying the founding homozygous
      nonsense mutation.
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three were homozygotes and three were compound heterozygotes"
    explanation: >
      Confirms both homozygous and compound-heterozygous biallelic genotypes
      cause disease across an ethnically diverse cohort.
pathophysiology:
- name: CERKL Biallelic Loss-of-Function
  biological_scale: MOLECULAR
  description: >
    Biallelic loss-of-function variants (nonsense, frameshift, splice, or
    damaging missense) eliminate or severely reduce functional CERKL protein.
    CERKL is structurally related to ceramide kinase but has no demonstrated
    catalytic activity toward ceramide or any other identified substrate, so
    disease variants act through simple loss of the protein's
    (non-catalytic) protective function rather than through a gain-of-function
    or dominant-negative mechanism.
  evidence:
  - reference: PMID:14681825
    reference_title: "Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients from the RP26 family bear a homozygous mutation in exon 5, which generates a premature termination codon."
    explanation: >
      Identifies the founding premature-termination-codon variant causing
      complete loss of CERKL protein function.
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As yet, no kinase activity is reported for CERKL and its function remains unclear"
    explanation: >
      Confirms CERKL has no demonstrated catalytic kinase activity despite
      its ceramide-kinase homology, so disease variants cause loss of an
      unconventional, non-catalytic protective function.
  downstream:
  - target: Loss of CERKL-Mediated Protection Against Oxidative Stress
    description: >-
      Loss of CERKL protein removes its protective effect against
      oxidative-stress-induced apoptosis in photoreceptors and other retinal
      cells.
- name: Loss of CERKL-Mediated Protection Against Oxidative Stress
  biological_scale: MOLECULAR
  description: >
    Wild-type CERKL protects cultured cells from apoptosis induced by
    oxidative stress; the RP-causing truncated R257X mutant does not. Loss of
    this protective function is proposed to tilt photoreceptors -- cells with
    high metabolic demand and chronic light-driven oxidative burden -- toward
    apoptosis.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: DECREASED
  evidence:
  - reference: PMID:19158957
    reference_title: "Overexpression of CERKL, a gene responsible for retinitis pigmentosa in humans, protects cells from apoptosis induced by oxidative stress."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CERKL (but not the RP R257X mutant) exerts a protective role in cells against oxidative stress, consistent with RP mutations impairing the normal protein function in photoreceptors and thus tilting the balance toward apoptosis."
    explanation: >
      Directly demonstrates loss of oxidative-stress protection by an
      RP-causing truncating variant, contrasted with protective wild-type
      CERKL.
  downstream:
  - target: Mitochondrial Fragmentation and Bioenergetic Dysfunction
    description: >-
      Loss of CERKL's protective function against oxidative stress is
      accompanied by disruption of mitochondrial structure and energy
      metabolism.
  - target: Dysregulated Autophagy
    description: >-
      Loss of CERKL function is accompanied by increased autophagy, part of
      the same organelle-stress response as mitochondrial fragmentation.
- name: Mitochondrial Fragmentation and Bioenergetic Dysfunction
  biological_scale: CELLULAR
  description: >
    CERKL isoforms localize in part to mitochondria in retinal neurons.
    Depletion of CERKL in knockdown/knockout mouse retinas causes
    mitochondrial fragmentation, altered mitochondrial distribution, and
    dysfunction of mitochondrial-dependent bioenergetics and metabolism,
    establishing CERKL as a regulator of mitochondrial dynamics in the retina.
  biological_processes:
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: INCREASED
  evidence:
  - reference: PMID:34048907
    reference_title: "CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism."
    explanation: >
      Mouse retina model directly links CERKL loss to mitochondrial
      fragmentation and bioenergetic/metabolic dysfunction.
  downstream:
  - target: Combined Rod and Cone Photoreceptor Apoptosis
    description: >-
      Impaired mitochondrial bioenergetics compromises photoreceptor
      survival, contributing to apoptosis in both rods and cones.
- name: Dysregulated Autophagy
  biological_scale: CELLULAR
  description: >
    CERKL depletion increases autophagy in retinal neurons, part of a
    disrupted organelle-quality-control response accompanying mitochondrial
    fragmentation.
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: INCREASED
  evidence:
  - reference: PMID:34048907
    reference_title: "CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The depletion of CERKL levels in CerklKD/KO(knockdown/knockout) mouse retinas cause increase of autophagy, mitochondrial fragmentation, alteration of mitochondrial distribution, and dysfunction of mitochondrial-dependent bioenergetics and metabolism."
    explanation: >
      The same mouse retina model demonstrates increased autophagy alongside
      mitochondrial fragmentation upon CERKL loss.
  downstream:
  - target: Combined Rod and Cone Photoreceptor Apoptosis
    description: >-
      Dysregulated autophagy compounds cellular stress, contributing to
      apoptosis in both rods and cones.
- name: Combined Rod and Cone Photoreceptor Apoptosis
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  biological_scale: CELLULAR
  description: >
    Unlike classic rod-first retinitis pigmentosa, CERKL loss produces
    electroretinographic patterns of similar severity in rods and cones in
    over half of tested patients, with the remainder split between rod-cone,
    cone-rod, and macular-dystrophy patterns -- reflecting combined loss of
    oxidative-stress protection and mitochondrial/autophagy dysfunction
    acting on both photoreceptor types rather than a strictly rod-first
    degenerative sequence.
  cell_types:
  - preferred_term: Retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: Retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:37331655
    reference_title: "CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern."
    explanation: >
      Multicenter natural-history cohort directly documents the mixed
      rod/cone electrophysiological pattern that does not fit the classic
      rod-cone/cone-rod dichotomy.
  downstream:
  - target: Macular and Peripheral Retinal Atrophy
    description: >-
      Progressive rod and cone loss produces the clinically observed macular
      and peripheral chorioretinal atrophy.
- name: Macular and Peripheral Retinal Atrophy
  biological_scale: TISSUE
  description: >
    The most common retinal finding is well-demarcated macular atrophy,
    often with a small preserved central island, accompanied in many
    patients by peripheral chorioretinal atrophic patches and variable
    intraretinal pigment deposition.
  evidence:
  - reference: PMID:37331655
    reference_title: "CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common retinal feature was well-demarcated areas of macular atrophy (57%)"
    explanation: >
      Establishes macular atrophy as the single most common retinal
      structural finding in the largest CERKL natural-history cohort.
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "peripheral areas of loss-of-signal consistent with the chorioretinal atrophic patches"
    explanation: >
      Documents peripheral chorioretinal atrophic patches accompanying
      central macular atrophy in an individual patient.
phenotypes:
- name: Reduced visual acuity
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:37331655
    reference_title: "CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent initial symptom was central vision loss (40%)"
    explanation: >
      Central vision loss is the most common initial presenting symptom, and
      longitudinal follow-up shows continued progressive acuity decline in
      most patients.
- name: Macular atrophy
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Macular atrophy
    term:
      id: HP:0007401
      label: Macular atrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:37331655
    reference_title: "CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common retinal feature was well-demarcated areas of macular atrophy (57%)"
    explanation: >
      Well-demarcated macular atrophy is the single most common retinal
      structural finding in the largest natural-history cohort to date.
- name: Abnormal electroretinogram
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  frequency: VERY_FREQUENT
  reports_on:
  - target: Combined Rod and Cone Photoreceptor Apoptosis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Abnormal ERG (whichever rod/cone/mixed pattern) measures the degree
      and distribution of photoreceptor dysfunction from ongoing rod and
      cone apoptosis.
  evidence:
  - reference: PMID:37331655
    reference_title: "CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern."
    explanation: >
      Every electrophysiologically assessed patient showed an abnormal
      pattern, split across four distinct dysfunction patterns rather than
      a single classic RP pattern.
- name: Nyctalopia
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  frequency: FREQUENT
  evidence:
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterised by symptoms of nyctalopia, peripheral visual field loss with a clinical appearance of intraretinal bone spicule pigmentation, pale discs and attenuated vasculature"
    explanation: >
      Nyctalopia is documented as a presenting symptom in this
      multi-ethnic CERKL cohort, consistent with the RP-pattern subset of
      the phenotype spectrum.
- name: Spicular pigmentation of the retina
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Spicular pigmentation of the retina
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  frequency: FREQUENT
  evidence:
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Widespread intraretinal bone spicule pigmentation was noted primarily in the mid-periphery"
    explanation: >
      Documents intraretinal bone spicule pigmentation in an individual
      CERKL patient; variable across the cohort (two of six patients had no
      pigment deposition), consistent with FREQUENT rather than universal
      frequency.
- name: Chorioretinal atrophy
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distinct nummular RPE depigmentation in the mid-periphery with chorioretinal atrophic patches temporally"
    explanation: >
      Documents peripheral chorioretinal atrophic patches in an individual
      CERKL patient, accompanying the central macular atrophy.
genetic:
- name: CERKL
  gene_term:
    preferred_term: CERKL
    term:
      id: hgnc:21699
      label: CERKL
  notes: >
    CERKL (ceramide kinase-like) shares sequence homology with ceramide
    kinase (CERK) but has no demonstrated catalytic activity toward ceramide
    or any other confirmed substrate. CERKL is an uncommon overall cause of
    autosomal recessive retinitis pigmentosa but is a significant contributor
    in several founder populations. Variants are distributed across the
    entire gene with no significant mutational clustering.
  evidence:
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these reported populations, CERKL is a significant gene contributing to autosomal recessive RP; presumably due to a founder mutation effect."
    explanation: >
      Documents CERKL founder mutations as significant contributors to
      autosomal recessive RP in Finnish, Yemenite Jewish, Spanish, and
      Tunisian populations, contrasted with its rarity elsewhere.
prevalence:
- population: Multiple founder populations (Finnish, Yemenite Jewish, Spanish, Tunisian)
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No single quantitative prevalence estimate is available; CERKL is
    described qualitatively as an uncommon overall cause of autosomal
    recessive retinitis pigmentosa but a significant cause of disease in
    specific founder populations.
  evidence:
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CERKL mutations are an uncommon cause of arRP, but they are a significant cause of disease in populations with founder mutations"
    explanation: >
      States the qualitative prevalence picture: rare overall, significant
      in specific founder populations.
treatments:
- name: Low Vision Rehabilitation
  description: >-
    Supportive low-vision aids and rehabilitation; no approved
    disease-modifying or gene therapy currently exists for CERKL-related
    retinopathy, though its small (1599 bp) coding sequence and recessive
    inheritance make it a plausible future AAV gene-therapy target.
  treatment_term:
    preferred_term: low vision rehabilitation
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33322828
    reference_title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, there are no therapeutic strategies to correct or treat the retinal degeneration caused by mutations in CERKL."
    explanation: >
      Confirms no disease-modifying treatment currently exists.
- name: Genetic Counseling
  description: Genetic counseling addressing autosomal recessive inheritance
    and recurrence risk.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
references:
- reference: PMID:14681825
  title: "Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26)."
- reference: PMID:19158957
  title: "Overexpression of CERKL, a gene responsible for retinitis pigmentosa in humans, protects cells from apoptosis induced by oxidative stress."
- reference: PMID:34048907
  title: "CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina."
- reference: PMID:37331655
  title: "CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History."
- reference: PMID:33322828
  title: "Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL."
📚

References & Deep Research

References

5
PMID:14681825
Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26).
No top-level findings curated for this source.
PMID:19158957
Overexpression of CERKL, a gene responsible for retinitis pigmentosa in humans, protects cells from apoptosis induced by oxidative stress.
No top-level findings curated for this source.
PMID:34048907
CERKL, a retinal dystrophy gene, regulates mitochondrial function and dynamics in the mammalian retina.
No top-level findings curated for this source.
PMID:37331655
CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History.
No top-level findings curated for this source.
PMID:33322828
Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL.
No top-level findings curated for this source.