Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa.
Invest Ophthalmol Vis Sci
; 57(8): 3601-9, 2016 Jul 01.
Article
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| MEDLINE
| ID: mdl-27391550
ABSTRACT
PURPOSE:
To identify the genetic cause in five families with autosomal recessive retinitis pigmentosa, a genetic disorder involving retinal degeneration and visual loss with high genetic heterogeneity.METHODS:
We performed whole-genome single nucleotide polymorphism genotyping on 35 members from the five families to map the region of homozygosity shared by all patients. Whole-genome sequencing was then conducted on one of the patients and a novel variant was identified in POMGNT1 from the homozygous region, which was confirmed by Sanger sequencing and sequenced in all family members. Mutant and wild-type POMGNT1 were expressed in heterologous cells to assess enzyme activity.RESULTS:
A 1.8-Mb homozygous region was identified at 1p34-p33 shared by all 17 patients. Whole-genome sequencing revealed a novel missense mutation in POMGNT1 (c.359A>C, p.Leu120Arg) from this homozygous region, which was shown to co-segregate with disease phenotype. The mutant protein carrying this missense mutation showed an approximately 80% decrease in POMGNT1 enzyme activity compared with the wild type.CONCLUSIONS:
We identified a novel mutation in POMGNT1 that causes nonsyndromic autosomal recessive retinitis pigmentosa, adding to the genetic heterogeneity of this retinal disease. POMGNT1 encodes a glycosyltransferase in O-mannosyl glycosylation and was previously found to be responsible for a group of congenital muscular dystrophies called dystroglycanopathies. Our discovery suggests the involvement of O-mannosyl glycosylation in retinitis pigmentosa and presents an instance of POMGNT1 mutation that does not involve muscular dystrophy.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Retinitis Pigmentosa
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N-Acetilglucosaminiltransferasas
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Mutación Missense
Límite:
Adolescent
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Adult
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Aged
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Child
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Invest Ophthalmol Vis Sci
Año:
2016
Tipo del documento:
Article