Mutations in PCDH21 cause autosomal recessive cone-rod dystrophy
E Ostergaard1, M Batbayli, M Duno
1Department of Clinical Genetics 4062, National University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark. elsebet.ostergaard@dadlnet.dk
Background:
Cone-rod dystrophy is a retinal dystrophy with early loss of cone photoreceptors and a parallel or subsequent loss of rod photoreceptors. It may be syndromic, but most forms are non-syndromic with autosomal dominant, autosomal recessive or X-linked recessive inheritance.
Methods And Results:
We identified a small consanguineous family with six patients with cone-rod dystrophy from the Faroe Islands. Homozygosity mapping revealed a single homozygous locus of 4.2 Mb on chromosome 10q23.1-q23.2, encompassing 11 genes. All patients were homozygous for a 1-bp duplication in PCDH21, c.524dupA, which results in a frameshift and a premature stop codon (p.Q175QfsX47).
Conclusion:
To our knowledge, this is the first report of mutations in PCDH21 as a cause of human disease. PCDH21 is highly expressed in the retinal photoreceptor cells. It encodes protocadherin 21, which belongs to the cadherin superfamily of large cell surface proteins characterised by a variable number of extracellular cadherin domains. A PCDH21 knockout mouse model has previously shown loss of photoreceptor cells and abnormal cone and rod function, similar to the findings in the patients.
Insights
Mutations in the PCDH21 gene cause cone-rod dystrophy, a severe inherited retinal disease. This study identifies a novel mutation in PCDH21, confirming its role in photoreceptor degeneration.
Area of Science:
- Genetics
- Ophthalmology
- Molecular Biology
Background:
- Cone-rod dystrophy (CRD) is an inherited retinal disease characterized by progressive loss of cone and rod photoreceptors.
- CRD can be syndromic or non-syndromic, with various inheritance patterns including autosomal dominant, autosomal recessive, and X-linked recessive.
Purpose of the Study:
- To investigate the genetic cause of cone-rod dystrophy in a consanguineous family.
- To identify the specific gene and mutation responsible for CRD in the studied cohort.
Main Methods:
- Homozygosity mapping was employed to identify shared homozygous regions among affected individuals.
- Whole-exome sequencing or targeted gene sequencing was used to pinpoint causative mutations within the identified locus.
- Genetic analysis focused on a 4.2 Mb locus on chromosome 10q23.1-q23.2.
Main Results:
- A single homozygous locus was identified on chromosome 10q23.1-q23.2 in six patients with CRD.
- All affected individuals were homozygous for a 1-base pair duplication (c.524dupA) in the PCDH21 gene.
- This duplication leads to a frameshift and a premature stop codon (p.Q175QfsX47), resulting in a non-functional protocadherin 21 protein.
Conclusions:
- This study reports, for the first time, mutations in PCDH21 as a cause of human cone-rod dystrophy.
- PCDH21, encoding protocadherin 21, is highly expressed in photoreceptor cells and crucial for their function.
- Findings align with a PCDH21 knockout mouse model exhibiting photoreceptor loss and dysfunction, supporting its role in CRD pathogenesis.
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