guanosine-diphosphate-mannose and Developmental-Disabilities

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[

Topics: Amino Acid Sequence; Brain Diseases; Child; Congenital Abnormalities; Developmental Disabilities; Female; Fibroblasts; Fucosyltransferases; Genetic Variation; Glycosylation; Guanosine Diphosphate Fucose; Guanosine Diphosphate Mannose; Humans; Male; Muscle Hypotonia; Phosphotransferases (Alcohol Group Acceptor); Seizures; Sequence Alignment; Skin; Ubiquitin