Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD).
Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder that is caused by mutations in the subunits of the branched-chain α-ketoacid dehydrogenase (BCKD) complex. BCKD is a mitochondrial complex encoded by four nuclear genes (BCKDHA, BCKDHB, DBT, and DLD) and is involved in the metabolism of branched-chain amino acids (BCAAs). In this study, we investigated the DNA sequences of BCKDHA, BCKDHB and DBT genes for mutations in a Chinese newborn with the classic form of MSUD and predicted the associated conformational changes using molecular modeling. We identified two previously unreported mutations in the BCKDHB gene, R170H (c.509G>A) in exon 5 and Q346R (c.1037 A>G) in exon 9. In silico analysis of the two novel missense mutations revealed that the mutation R170H-β alters the spatial orientation with both Y195-β' and S206-α, which results in unstable β-β' assembly and an unstable K(+) ion binding loop of the α subunit, respectively; The Q346R mutation is predicted to disrupt the spatial conformation between Q346-β and I357-β', which reduces the affinity of the β-β' subunits. These results indicate that R170-β and Q346-β are crucial for the activity of the E1 component. These two novel mutations, R170H and Q346R result in the patient's clinical manifestation of the classic form of MSUD.
Department of Clinical Genetics, China Medical University affiliated Shengjing Hospital, Shenyang, 110004, People's Republic of China. wangyp@sj-hospital.org
Yue-Ping
YP
Wang
Man-Long
ML
Qi
Ting-Ting
TT
Li
Yun-Jing
YJ
Zhao
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000737:chemistry / Q000235:genetics*; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002681:China; D004247:DNA / Q000235:genetics; D004795:Enzyme Stability; D005091:Exons; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008375:Maple Syrup Urine Disease / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits
D021122:Protein Subunits; D004247:DNA; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)