Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.
Am J Hum Genet
; 103(6): 1030-1037, 2018 12 06.
Article
en En
| MEDLINE
| ID: mdl-30503518
ABSTRACT
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-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Anomalías Congénitas
/
Variación Genética
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Fosfotransferasas (Aceptor de Grupo Alcohol)
Límite:
Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hum Genet
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos