A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the ER quality control in the mechanism of some β3GalT6-pathy mutations

ABSTRACT

Al-Gazali syndrome encompasses several clinical features including prenatal growth retardation, large joints contractures with camptodactyly, bilateral talipes equinovarus, small mouth, anterior segment anomalies of the eyes, and early lethality. Recently, a baby with features very similar to Al-Gazali syndrome was found to have compound heterozygous variants in B3GALT6. This gene encodes Beta-1,3-galactosyltransferase 6 (β3GalT6), an essential component of the glycosaminoglycan synthesis pathway. Pathogenic variants in B3GALT6 have also been shown to cause Ehlers-Danlos syndrome spondylodysplastic type (spEDS-B3GALT6) and spondylo-epimetaphyseal dysplasia with joint laxity type I (SEMD-JL1). In 2017 a new international classification of EDS included these 2 conditions together with the child reported to have features similar to Al-Gazali syndrome under spondylodysplastic EDS (spEDS). We report a disease-causing variant c.618C>G, p.(Cys206Trp) in one patient originally described as Al-Gazali syndrome and reported in 1999. We evaluated the involvement of the Endoplasmic-reticulum-associated protein degradation (ERAD), in the pathogenesis of thirteen B3GALT6 variants. Retention in ER was evident in six of them while the c.618C>G, p.(Cys206Trp) and the other six variants trafficked normally. Our findings confirm the involvement of B3GALT6 in the pathogenesis of Al-Gazali syndrome and suggest that Al-Gazali syndrome represents the severe end of the spectrum of the phenotypes caused by pathogenic variants in this gene.

from Genetics via xlomafota13 on Inoreader http://ift.tt/2nWyDtB
via IFTTT