Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD)

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• 作者：Yue-Ping Wang^a ; ^{wangyp@sj-hospital.org} ; Man-Long Qi^a ; Ting-Ting Li^a ; Yun-Jing Zhao^b
• 关键词：MSUD ; maple syrup urine disease ; BCKD ; branched-chain 2-keto acid dehydrogenase ; BCAA ; branched-chain amino acid ; BCKAs ; branched-chain 伪-ketoacid ; E1 ; branched-chain 伪-keto-acid decarboxylase ; E2 ; a dihydrolipoyl transacylase ; E3 ; a dihydrolipoamide de
• 刊名：Gene
• 出版年：2012
• 期刊代码：73_03781119
• 类别：bio
• 出版时间：25 April, 2012
• 卷：498
• 期：1
• 页码：112-115
• 文件大小：944 K

摘要

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder that is caused by mutations in the subunits of the branched-chain 伪-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.509 G > 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-尾 alters the spatial orientation with both Y195-尾鈥?and S206-伪, which results in unstable 尾-尾鈥?assembly and an unstable K⁺ ion binding loop of the 伪 subunit, respectively; The Q346R mutation is predicted to disrupt the spatial conformation between Q346-尾 and I357-尾鈥? which reduces the affinity of the 尾-尾鈥?subunits. These results indicate that R170-尾 and Q346-尾 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.