Identification of a novel MKS locus defined byTMEM107mutation

Abstract

Meckel-Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation.

In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

“…Some JSRD fibroblasts had abnormally long dysmorphic cilia similar to those observed recently in TMEM107 mutant fibroblasts(Shaheen et al, 2015). Intracellular cilia lacking the ciliary membrane in JSRD fibroblasts had been previously observed in the Cep290 -knockout mouse(Rachel et al, 2015).…”

TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome

“…Causality of the mutations identified here to JBTS and OFDVI is supported by very recent reports of additional TMEM107 mutations linked to MKS and OFD 30, 31. Furthermore, we show that ciliopathy proteins are anchored at the TZ membrane, and display periodic radial and axial distributions at the TZ core and membrane.…”

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

“…The MKS complex derives its name from Meckel–Gruber syndrome (MKS), an extremely severe ciliopathy, leading to perinatal lethality and characterized by occipital encephalocele, polycystic kidneys, and polydactyly (Hildebrandt et al 2011). MKS can arise from mutations in MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, TMEM231, KIF14, TCTN3, and TMEM107 (Thomas et al 2012; Shaheen et al 2013; Filges et al 2014; Valente et al 2014; Roberson et al 2015; Shaheen et al 2015). Of these, all except RPGRIP1L, NPHP3, and KIF14 encode identified components of the MKS complex (Chih et al 2011; Dowdle et al 2011; Garcia-Gonzalo et al 2011; Sang et al 2011; Roberson et al 2015; Lambacher et al 2016).…”