Clinical, biochemical, and molecular findings in three patients with 3-hydroxyisobutyric aciduria.
3-Hydroxyisobutyric aciduria is a rare entity and affected individuals display a range of clinical manifestations including dysmorphic features and neurodevelopmental problems in the majority of patients. Here, we present two novel patients with 3-hydroxyisobutyric aciduria. To our knowledge, these are the 11th and 12th cases of 3-hydroxyisobutyic aciduria reported. It is believed that a deficiency in 3-hydroxyisobutyrate dehydrogenase is the most likely cause of this disorder. Measurement of 3-hydroxyisobutyrate dehydrogenase activity in fibroblasts homogenates of the two newly identified patients and a previously reported patient, however, revealed similar activities as in control fibroblasts. Since other enzymes with overlapping substrate specificity could conceal abnormal 3-hydroxyisobutyrate dehydrogenase activity, we cloned a candidate human cDNA for 3-hydroxyisobutyrate dehydrogenase (HIBADH). By heterologous expression in Escherichia coli, we showed that the product of the HIBADH gene indeed displays 3-hydroxyisobutyrate dehydrogenase activity. Mutation analysis of the corresponding gene in the patients suffering from 3-hydroxyisobutyric aciduria revealed no mutations. We conclude that HIBADH is not the causative gene in 3-hydroxyisobutyric aciduria.
Loupatty
Ference J
FJ
Department of Clinical Chemistry and Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
van der Steen
Annemarie
A
Ijlst
Lodewijk
L
Ruiter
Jos P N
JP
Ofman
Rob
R
Baumgartner
Matthias R
MR
Ballhausen
Diana
D
Yamaguchi
Seiji
S
Duran
Marinus
M
Wanders
Ronald J A
RJ
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D006885:Hydroxybutyrates / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014633:Valine / Q000378:metabolism
D006885:Hydroxybutyrates; D011993:Recombinant Fusion Proteins; D004247:DNA; D000429:Alcohol Oxidoreductases; C021398:3-hydroxyisobutyrate dehydrogenase; D014633:Valine