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Mutations in human IFT140 cause non-syndromic retinal degeneration

Jul 27, 2015

Mingchu Xu, Lizhu Yang, Feng Wang, Huajin Li,3 Xia Wang, Weichen Wang, Zhongqi Ge, Keqing Wang, Li Zhao, Hui Li, Yumei Li, Ruifang Sui, and Rui Chen | Human Genetics | 28 July 2015 | Vol 134 | 1069–1078 | ncbi.nlm.nih.gov/pmc/articles/PMC4565766/


In this study, we totally investigated seven unrelated non-syndromic RD patients, including five RP and two LCA cases. Among them, five of them are Han Chinese and the remaining two are of European ethnicity diagnosed in United States. The index case we investigated, SRF71, is a 43-year-old male RP patient of Han Chinese ethnicity. . . 

Preliminary screening by retinal capture sequencing found no causative mutations in known RP-causing genes. WES data show that he has biallelic variants in IFT140,  . . .


Abstract

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members’ DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease.


Introduction

Leber congenital amaurosis (LCA, MIM# 204000) and retinitis pigmentosa (RP, MIM# 268000) are two types of inherited retinal degenerative diseases. LCA is featured by congenital or infantile-onset vision loss, nystagmus and absent electroretinogram (ERG) signals. RP is a more common and variable form of retinal degeneration (RD) and its onset ranges from childhood to mid-adulthood (Hartong et al. 2006). Both LCA and RP are highly genetically heterogeneous. To date, at least 21 LCA-causing and 64 RP-causing genes have been identified (RetNet, the Retinal Information Network) (SP Daiger). Mutations in these genes account for about 70 % of LCA and 60 % of RP cases, respectively, suggesting that the molecular basis of a significant number of cases is yet to be discovered (Wang et al. 2013, 2014).


Retinal degenerative disorders can be syndromic, in which case patients develop symptoms in other systems in addition to their ocular abnormalities. This phenomenon is frequently seen in ciliopathies with retinal involvement since photoreceptors develop highly specialized cilia structure and ciliated cells are widespread in the human body (Hildebrandt et al. 2011). Mutations in ciliary genes were identified in a number of syndromes with RD including Senior–Løken syndrome (SLSN, MIM# 266900) (Otto et al. 2005), Joubert syndrome (JBTS, MIM# 213300) (Dixon-Salazar et al. 2004), Bardet–Biedl syndrome (BBS, MIM#209900) (Mykytyn et al. 2001).


It has also been reported that mutations in syndromic ciliopathy genes can lead to non-syndromic LCA or RP. For example, IQCB1 mutations were originally identified to cause SLSN (Otto et al. 2005), but certain IQCB1 mutant alleles were found to cause LCA without renal symptoms (Estrada-Cuzcano et al. 2011). Similarly, while mutations in CEP290, a cilia basal body gene, can cause a series of syndromic ciliopathies including JBTS and BBS (Baala et al. 2007; Sayer et al. 2006; Valente et al. 2006), it is also a major contributor to non-syndromic LCA cases (den Hollander et al. 2006). Given the fact that cilia are responsible for numerous biological processes in multiple tissues, the diverse genotype–phenotype correlations observed by these studies can be explained by a combination of multi-functional nature of these ciliary genes and differential damaging effect of their mutant alleles.


Intraflagellar transport (IFT) is a biological process by which various proteins are transported along the microtubule-based cilia (Rosenbaum and Witman 2002). Specifically, the IFT-A complex is responsible for the return of proteins from the ciliary tip (Absalon et al. 2008). Defects in IFT-A particles have already been associated with a spectrum of human ciliopathies. Mutations in one IFT-A complex component, WDR19, were reported to cause cranioectodermal dysplasia (CED, MIM# 614378) (Bredrup et al. 2011), nephronophthisis (NPHP, MIM# 614377) (Halbritter et al. 2013b) as well as non-syndromic retinitis pigmentosa (Coussa et al. 2013). Similarly, mutations in IFT140, another IFT-A complex gene, were known to cause two types of rare recessive ciliopathies: Mainzer–Saldino syndrome (MZSDS, MIM# 266920) and Jeune asphyxiating thoracic dystrophy (JATD, MIM# 208500) (Khan et al. 2014; Perrault et al. 2012; Schmidts et al. 2013). MZSDS is featured by cone-shaped epiphysis, chronic renal disease, abnormality of the proximal femur and RD (Beals and Weleber 2007; Giedion 1979). JATD patients show constricted thoracic cage, short-limbed short stature, polydactyly and often develop multi-organ disorders including retinal abnormalities (Bard et al. 1978; de Vries et al. 2010; Oberklaid et al. 1977). Since both WDR19 and IFT140 are linked to ciliopathies with retinal involvement, it is intriguing for us to know, whether IFT140 defects, like WDR19 mutations, can also cause non-syndromic RD.


In this study, through whole exome sequencing (WES), mutations in IFT140 have been identified in seven patients diagnosed with non-syndromic LCA or RP. These patients come from diverse ethnicities and account for about 1 % of non-syndromic RD cases. Our results highlight a novel genotype–phenotype correlation of a ciliary gene, which can improve the molecular diagnosis of retinal degenerative diseases and our understanding of intraflagellar transport in the retina.



 

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