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

摘要

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 spondyloepimetaphyseal 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 1 patient originally described as Al‐Gazali syndrome and reported in 1999. We evaluated the involvement of the endoplasmic reticulum‐associated protein degradation, in the pathogenesis of 13 B3GALT6 variants. Retention in endoplasmic reticulum was evident in 6 of them while the c.618C G, p.(Cys206Trp) and the other 6 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.