Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases

Abstract

Background Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snaillike configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD. Object To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group. Methods and results We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases. Conclusion Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.

Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia

“…SD demonstrates locus heterogeneity and had previously been shown to be caused by mutations in SLC35D1 , encoding an ER-resident sugar transporter (Hiraoka et al, 2007, Furuichi et al, 2009). SD is distinguished from other severe skeletal dysplasias by the presence on radiographs of a medial projection from the ilia that resembles a snail.…”

CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant

“…Both are caused by deficiency of enzymes involved in the metabolism of chondroitin sulfate, an essential component of cartilage matrix. We have previously shown that a functional defect of the solute carrier-35 D1 (SLC35D1) caused a severe skeletal dysplasia in mouse and human 27 28. SLC35D1 is a nucleotide sugar transporter that transports UDP-N-acetylgalactosamine and UDP-glucronic acid from the cytoplasm into the ER 29 30.…”

N-acetylglucosamine modification in the lumen of the endoplasmic reticulum

“…A potential candidate for ER UDP-GlcNAc transport is SLC35D1. This protein transports UDP-GlcUA, UDP-GalNAc, and UDP-GlcNAc [43,44]. SLC35D1 knockout resulted in diminished chondroitin sulfate synthesis and defective cartilage and skeletal development in mice [44].…”