<i>RPE65</i> Mutations in Two Japanese Families with Leber Congenital Amaurosis

Katagiri, Satoshi; Hayashi, Takaaki; Kondo, Mineo; Tsukitome, Hideyuki; Yoshitake, Kazutoshi; Akahori, Masakazu; Ikeo, Kazuho; Tsuneoka, Hiroshi; Iwata, Takeshi

doi:10.3109/13816810.2014.991931

Cited by 25 publications

(10 citation statements)

References 22 publications

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“…(32,33). This cohort within the National Health system of Costa Rica suggests a higher prevalence of RPE65 mutations than has been estimated in other populations around the world (31,34,35,36,37,38,39,40), though some studies have suggested population specific increases in RPE65 mutation prevalence (31,41). This study identified four recurrent RPE65 mutations, at least one of which was seen in 29 out of 30 cases (97%), and 20 out of 21 families (95%).…”

Section: Discussionmentioning

confidence: 66%

A high prevalence of biallelicRPE65mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

Glen

Peterseim

Badilla

et al. 2019

Ophthalmic Genetics

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Background: Leber Congenital Amaurosis (LCA) and Early Onset Retinal Dystrophy (EORD), are primary causes of inherited childhood blindness. Both are autosomal recessive diseases, with more than 25 genes explaining approximately ~70% of cases. However, the genetic cause for many cases remains unclear. Sequencing studies from genetically isolated populations with increased prevalence of a disorder has proven useful for rare variant studies, making Costa Rica an ideal place to study LCA/EORD genetics. Materials and Methods: Twenty-eight affected children (25 LCA, three EORD) and their immediate family members, totaling 52 individuals (30 affected) from 22 families, were sequenced. Whole exome sequencing was performed on all affected individuals. Available parents were analyzed either by WES or Sanger sequencing to determine transmission. Results: All affected individuals demonstrated compound heterozygous or homozygous mutations in known Inherited Retinal Disease (IRD) genes. Twelve variants were identified in at least one individual in three genes, RDH12, RPE65, and USH2A. Four recurrent RPE65 mutations were observed in 97% of individuals and 95% of families. All patients with LCA and two of the three individuals with EORD had biallelic mutations in RPE65; one child with EORD had a homozygous RDH12 mutation. Conclusions: These data suggest that the majority of LCA/EORD in Costa Rica is due to four founder effects in RPE65 which have been maintained in this genetically isolated population. This finding is of great clinical significance due to the availability of gene therapy recently approved in US and European Union for patients with biallelic RPE65 deficits.

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Section: Discussionmentioning

confidence: 66%

A high prevalence of biallelicRPE65mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

Glen

Peterseim

Badilla

et al. 2019

Ophthalmic Genetics

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“…Therefore, biallelic RPE65 mutations contributed to approximately 3.0% (8/269) of LCA and 0.8% (18/2133) of HRD cases. Clinically, diseases in 13 of the 18 families could be classified as LCA or EORD, which are common phenotypes previously reported to be associated with RPE65 mutations (Gu et al 1997;Marlhens et al 1997;Morimura et al 1998;Thompson et al 2000;Simovich et al 2001;Yzer et al 2003;Booij et al 2005;El Matri et al 2006;Simonelli et al 2007;Li et al 2009;Xu et al 2012;Kabir et al 2013;Verma et al 2013;Astuti et al 2016;Katagiri et al 2016). In the remaining five families with biallelic RPE65 mutations, we unexpectedly found that the phenotypes were FA-like changes in four families and high hyperopia in one family.…”

Section: Discussionmentioning

confidence: 91%

“…; Katagiri et al. ). In the remaining five families with biallelic RPE65 mutations, we unexpectedly found that the phenotypes were FA‐like changes in four families and high hyperopia in one family.…”

Section: Discussionmentioning

confidence: 97%

RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye diseases in China

Xiao

Zhen

et al. 2019

Acta Ophthalmologica

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Purpose Retinoid isomerohydrolase RPE65 has received a tremendous amount of attention due to successful clinical gene therapy for Leber congenital amaurosis (LCA) cases caused by RPE65 mutations. This study aimed to evaluate the frequency of RPE65 mutations and the associated phenotypes based on exome sequencing. Methods RPE65 variants were collected from exome sequencing data obtained from 2133 probands with different forms of hereditary retinal degeneration (HRD). Clinical data were collected from probands with homozygous or compound heterozygous variants in RPE65. Associated phenotypes were characterized based on clinical data. Results Biallelic RPE65 mutations were detected in 18 families, including eight with LCA, five with early‐onset retinal degeneration, four with fundus albipunctatus‐like (FA‐like) changes and one with high hyperopia. These cases accounted for approximately 3.0% (8/269) of LCA and 0.8% (18/2133) of HRD cases. An almost identical FA‐like change was identified in seven patients from four unrelated families with RPE65 mutations. Classification of mutations suggested that FA‐like changes may be associated with biallelic missense mutations in RPE65. Conclusion Fundus albipunctatus‐like (FA‐like) change, a common characteristic fundus sign in RPE65 biallelic mutations, was unexpected but was confirmed by the finding that affected siblings from different families exhibited similar phenotypes. These results enrich our understanding of RPE65 mutation frequencies and their associated phenotypic variants.

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“…Full-field electroretinography using a light-emitting diode with a built-in electrode (LE-4000, Tomey, Nagoya, Japan) was recorded in accordance with the protocols of the International Society for Clinical Electrophysiology of Vision 34 . The procedure and conditions used in this study have been previously reported 35 , 36 .…”

Section: Methodsmentioning

confidence: 99%

Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome

Katagiri

Hayashi

Yoshitake

et al. 2018

Sci Rep

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Senior Løken syndrome (SLS) is a heterogeneous disorder characterized by severe retinal degenerations and juvenile-onset nephronophthisis. Genetic variants in ten different genes have been reported as the causes of SLS. Clinical evaluation of a patient with SLS and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts (6 bps deletion in the last of exon 17 [p.V543_K544del] and exons 17 and 18 skipping [p.D480E, S481_K610del]). Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein. In conclusion, we identified compound heterozygous splice site variants of SCLT1 in a patient with a new form of ciliopathies that exhibits clinical features of SLS.

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RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis

Abstract: By using whole-exome sequencing analysis, three RPE65 mutations were identified in two Japanese patients with LCA. This approach would be useful for identification of disease-causing mutations of LCA.

Cited by 25 publications

References 22 publications

A high prevalence of biallelicRPE65mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

A high prevalence of biallelicRPE65mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy

RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye diseases in China

Compound heterozygous splice site variants in the SCLT1 gene highlight an additional candidate locus for Senior-Løken syndrome

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