Mor Hanany1, Sapir Shalom1,2, Tamar Ben-Yosef3 and Dror Sharon1 1Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120001, Israel 2Department of Military Medicine and "Tzameret," Faculty of Medicine, Hebrew University of Jerusalem and Medical Corps, Israel Defense Forces, Jerusalem 9112102, Israel 3Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel Correspondence: dror.sharon1{at}mail.huji.ac.il

Hebrews

Rappaport

10.1101/cshperspect.a041277

Cite

Citations (9)

FAM161A, associated with retinitis pigmentosa, is a component of the cilia-basal body complex and interacts with proteins involved in ciliopathies

Human Molecular Genetics (2012)

Silvio Alessandro Di Gioia Stef J.F. Letteboer Corinne Kostic Dikla Bandah-Rozenfeld Lisette Hetterschijt

Retinitis pigmentosa (RP) is a retinal degenerative disease characterized by the progressive loss of photoreceptors. We have previously demonstrated that RP can be caused by recessive mutations in the human FAM161A gene, encoding a protein with unknown function that contains a conserved region shared only with a distant paralog, FAM161B. In this study, we show that FAM161A localizes at the base of the photoreceptor connecting cilium in human, mouse and rat. Furthermore, it is also present at the ciliary basal body in ciliated mammalian cells, both in native conditions and upon the expression of recombinant tagged proteins. Yeast two-hybrid analysis of binary interactions between FAM161A and an array of ciliary and ciliopathy-associated proteins reveals direct interaction with lebercilin, CEP290, OFD1 and SDCCAG8, all involved in hereditary retinal degeneration. These interactions are mediated by the C-terminal moiety of FAM161A, as demonstrated by pull-down experiments in cultured cell lines and in bovine retinal extracts. As other ciliary proteins, FAM161A can also interact with the microtubules and organize itself into microtubule-dependent intracellular networks. Moreover, small interfering RNA-mediated depletion of FAM161A transcripts in cultured cells causes the reduction in assembled primary cilia. Taken together, these data indicate that FAM161A-associated RP can be considered as a novel retinal ciliopathy and that its molecular pathogenesis may be related to other ciliopathies.

Ciliopathies

Ciliopathy

Ciliogenesis

Basal body

Motile cilium

Intraflagellar Transport

Bardet–Biedl Syndrome

10.1093/hmg/dds368

Cite

Citations (57)

BBS1 Mutations in a Wide Spectrum of Phenotypes Ranging From Nonsyndromic Retinitis Pigmentosa to Bardet-Biedl Syndrome

Archives of Ophthalmology (2012)

Alejandro Estrada‐Cuzcano Robert K. Koenekoop Audrey Sénéćhal Elfride De Baere Thomy de Ravel

Objective

To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP).

Methods

Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment.

Results

In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed.

Conclusions

Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype.

Clinical Relevance

It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.

Proband

Bardet–Biedl Syndrome

Compound heterozygosity

10.1001/archophthalmol.2012.2434

Cite

Citations (120)

A non‐ancestral RPGR missense mutation in families with either recessive or semi‐dominant X‐linked retinitis pigmentosa

American Journal of Medical Genetics Part A (2007)

Eyal Banin Liliana Mizrahi‐Meissonnier Ruhama Neis Shira Silverstein I Magyar

Abstract Most X‐linked diseases show a recessive pattern of inheritance in which female carriers are unaffected. In X‐linked retinitis pigmentosa (XLRP), however, both recessive and semi‐dominant inheritance patterns have been reported. We identified an Israeli family with semi‐dominant XLRP due to a missense mutation (p.G275S) in the RPGR gene. The mutation was previously reported in two Danish families with recessive XLRP. Obligate carriers from the two Danish families had no visual complaints and normal to slightly reduced retinal function, while those from the Israeli family suffered from high myopia, low visual acuity, constricted visual fields, and severely reduced electroretinogram (ERG) amplitudes. The disease‐related RPGR haplotype of the Israeli family was found to be different from the one found in the two Danish families, indicating that the mutation arose twice independently on different X‐chromosome backgrounds. A series of genetic analyses excluded skewed X‐inactivation pattern, chromosomal abnormalities, distorted RPGR expression level, and mutations in candidate genes as the cause for the differences in disease severity of female carriers. To the best of our knowledge, this is the first detailed analysis of an identical mutation causing either a recessive or a semi‐dominant X‐linked pattern of disease in different families. Our results indicate that an additional gene (or genes), linked to RPGR , modulate disease expression in severely affected carriers. These may be related to the high myopia concomitantly found in affected carriers from the Israeli family. © 2007 Wiley‐Liss, Inc.

X-linked recessive inheritance

Genetic linkage

10.1002/ajmg.a.31642

Cite

Citations (38)

Genetic causes of inherited retinal diseases among Israeli Jews of Ethiopian ancestry.

PubMed (2023)

Tamar Ben Yosef Eyal Banin Elana Chervinsky Stavit A. Shalev Rina Leibu

This study sought to describe the phenotype frequency and genetic basis of inherited retinal diseases (IRDs) among a nationwide cohort of Israeli Jewish patients of Ethiopian ancestry.Patients' data-including demographic, clinical, and genetic information-were obtained through members of the Israeli Inherited Retinal Disease Consortium (IIRDC). Genetic analysis was performed by either Sanger sequencing for founder mutations or next-generation sequencing (targeted next-generation sequencing or whole-exome sequencing).Forty-two patients (58% female) from 36 families were included, and their ages ranged from one year to 82 years. Their most common phenotypes were Stargardt disease (36%) and nonsyndromic retinitis pigmentosa (33%), while their most common mode of inheritance was autosomal recessive inheritance. Genetic diagnoses were ascertained for 72% of genetically analyzed patients. The most frequent gene involved was ABCA4. Overall, 16 distinct IRD mutations were identified, nine of which are novel. One of them, ABCA4-c.6077delT, is likely a founder mutation among the studied population.This study is the first to describe IRDs' phenotypic and molecular characteristics in the Ethiopian Jewish community. Most of the identified variants are rare. Our findings can help caregivers with clinical and molecular diagnosis and, we hope, enable adequate therapy in the near future.

ABCA4

Sanger sequencing

Founder effect

Stargardt disease

Exome

Source

Cite

Citations (4)

Dichotomy of single-nucleotide polymorphism haplotypes in olfactory receptor genes and pseudogenes

Nature Genetics (2000)

Yoav Gilad Daniel Segrè Karl Skorecki Michael W. Nachman Doron Lancet

Pseudogene

10.1038/79957

Cite

Citations (87)