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Lina Zelinger, Carmen Ayuso, Eyal Banin, Dror Sharon; A Missesne Mutation in the Acetyl-CoA Carboxylase β Gene Involved in Lipid Metabolism is Associated with Autosomal Recessive Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3351.
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© ARVO (1962-2015); The Authors (2016-present)
The genetic cause of disease in our Israeli and Palestinian cohort is still unknown in most cases with autosomal recessive (AR) retinitis pigmentosa (RP). Aiming to identify additional genes associated with the disease, we used a combination of whole genome single nucleotide polymorphism (SNP) analysis followed by whole exome sequencing (WES) in a family of Iranian Jewish ancestry with ARRP.
Patients were evaluated clinically using visual function testing and electroretinography. Blood samples were obtained from patients and unaffected family members who agreed to participate in the study. Homozygosity mapping was performed using the Affymetrix 6.0 platform. WES was performed on the index case at Otogenetics with over 60M reads, 91% of which were mapped to exonic sequences. The identified mutation in the ACACB gene was verified by Sanger sequencing and screened in additional samples.
We recruited for the study a consanguineous family of Iranian Jewish origin (MOL0249) with three individuals affected with RP. Homozygosity mapping (HM) of the three patients revealed a single large (5 Mb) shared homozygous region on chromosome 12, containing 71 protein coding genes. A subsequent WES analysis revealed 304 homozygous variants within the region. Further analysis narrowed down the number of potential pathogenic changes to 32. Only 2 changes were within coding sequences and only one was predicted by online prediction software (Polyphen2 and MutationTaster) to be damaging: c.G4469A (p.R1490H) missense change in the Acetyl-CoA carboxylase β (ACACB) gene. The mutation cosegregated in the family with LOD score of 3.3. The Arg1490 amino acid is highly conserved throughout evolution. Acetyl-CoA carboxylase β is an enzyme in the metabolic pathway of lipids. It catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. It is suspected to be involved in the regulation of fatty acid oxidation, rather than biosynthesis.
We report here an association between a missense mutation in the ACACB gene and retinal degeneration. HM combined with WES allowed us to identify a possible new pathway that is involved in the phathogenicity of RP. This result, along with identification of genes such as DHDDS and ELOVL4, shows the importance of lipids and fatty acids in the proper function of the retina.
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