Biallelic GALM pathogenic variants cause a novel type of galactosemia
2018
Galactosemiais caused by
metabolic disturbancesat various stages of
galactosemetabolism, including deficiencies in enzymes involved in the
Leloir pathway(GALT, GALK1, and GALE). Nevertheless, the etiology of
galactosemiahas not been identified in a subset of patients. This study aimed to explore the causes of unexplained
galactosemia. Trio-based
exome sequencingand/or
Sanger sequencingwas performed in eight patients with unexplained congenital
galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. The highest blood
galactoselevels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding
galactose mutarotase, which catalyzes epimerization between β- and α-D-
galactosein the first step of the
Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Biallelic GALM pathogenic variants cause
galactosemia, suggesting the existence of type IV
galactosemia.
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