Mutations in the translocon-associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation.

Autor:	Ng BG; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Lourenço CM; Clinical Genetics and Neurogenetics, Centro Universitario Estacio de Ribeirao Preto, Ribeirao Preto, Brazil., Losfeld ME; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Buckingham KJ; Department of Pediatrics, University of Washington, Seattle, Washington., Kircher M; Department of Genome Sciences, University of Washington, Seattle, Washington., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, Washington., Shendure J; Department of Genome Sciences, University of Washington, Seattle, Washington.; Howard Hughes Medical Institute, University of Washington, Seattle, Washington., Bamshad MJ; Department of Pediatrics, University of Washington, Seattle, Washington.; Department of Genome Sciences, University of Washington, Seattle, Washington., Freeze HH; Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
Jazyk:	angličtina
Zdroj:	Journal of inherited metabolic disease [J Inherit Metab Dis] 2019 Sep; Vol. 42 (5), pp. 993-997. Date of Electronic Publication: 2019 Apr 16.
DOI:	10.1002/jimd.12091
Abstrakt:	The translocon-associated protein (TRAP) complex facilitates the translocation of proteins across the endoplasmic reticulum membrane and associates with the oligosaccharyl transferase (OST) complex to maintain proper glycosylation of nascent polypeptides. Pathogenic variants in either complex cause a group of rare genetic disorders termed, congenital disorders of glycosylation (CDG). We report an individual who presented with severe intellectual and developmental disabilities and sensorineural deafness with an unsolved type I CDG, and sought to identify the underlying genetic basis. Exome sequencing identified a novel homozygous variant c.278_281delAGGA [p.Glu93Valfs*7] in the signal sequence receptor 3 (SSR3) subunit of the TRAP complex. Biochemical studies in patient fibroblasts showed the variant destabilized the TRAP complex with a complete loss of SSR3 protein and partial loss of SSR1 and SSR4. Importantly, all subunit levels were corrected by expression of wild-type SSR3. Abnormal glycosylation status in fibroblasts was confirmed using two markers proteins, GP130 and ICAM1. Our findings confirm mutations in SSR3 cause a novel CDG. A novel frameshift variant in the translocon associated protein, SSR3, disrupts the stability of the TRAP complex and causes a novel Congenital Disorder of Glycosylation. (© 2019 SSIEM.)
Databáze:	MEDLINE
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