Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1 , a Gene Implicated in Ubiquitination

Abstract

Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations.

Genetics of Reproductive Aging from Gonadal Dysgenesis through Menopause

“…Mutations in this gene have also been observed to be the causal factor for syndromic POI. 61 Hormones play an essential role in regulating folliculogenesis. The entire menstrual cycle is tightly regulated by the function of gonadotropin hormones and their receptors.…”

Targeted deletion of Nmnat1 in mouse retina leads to early severe retinal dystrophy

“…Sequencing studies have recently found that mutations in NMNAT1 can cause LCA and these constitute approximately 10% of unsolved cases (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). The majority of NMNAT1 mutations found in LCA patients are missense, with a small portion are nonsense and frameshift.…”

Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations

“…Over two million people worldwide are affected by inherited retinal degenerations (IRDs), a family of blinding diseases characterized by progressive death and dysfunction of primarily rod and cone photoreceptors 1,2 . Pathogenic variants (PVs) in over 270 genes have been associated with IRDs 3 , many of which were discovered recently by virtue of advances in sequencing technologies [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] . However, despite substantial progress in genetic methodologies, current strategies can genetically solve only about 55-60% of IRD cases [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] .…”

“…The remaining missing diagnoses are in part due to new, yet to be discovered IRD genes. However, PVs in each new disease gene are rare, affecting a handful of IRD patients [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] , suggesting that the missing genetic causality largely lies in the known IRD genes. A considerable proportion of these elusive PVs are due to structural variations (SVs) such as copy number variations (CNVs), or deep intronic variants that affect splicing 36,[39][40][41][42][43][44][45][46][47][48][49] , which are not readily available from the standard output of targeted next generation sequencing (NGS) pipelines.…”