Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population

Abstract

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder. This disorder is usually caused by mutations in any one of the genes; BCKDHA, BCKDHB and DBT, which represent E1α, E1β and E2 subunits of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, respectively. This study presents the molecular characterization of 31 MSUD patients. Twenty one mutations including 14 new mutations were identified. The BCKDHB gene was the most commonly affected (45.2%) compared to BCKDHA gene (16.1%) and DBT gene (38.7%). In silico webservers predicted all mutations were disease-causing. In addition, structural evaluation disclosed that all new missenses in BCKDHA, BCKDHB and DBT genes affected stability and formation of E1 and E2 subunits. Majority of the patients had neonatal onset MSUD (26 of 31). Meanwhile, the new mutation; c.1196C > G (p.S399C) in DBT gene was noted to be recurrent and found in 9 patients. Conclusion: Our findings have expanded the mutational spectrum of the MSUD and revealed the genetic heterogeneity among Malaysian MSUD patients. We also discovered the p.S399C from DBT gene was noted as a recurrent mutation in Malay community and it suggested the existence of common and unique mutation in Malay population.

Keywords: Autosomal recessive; BCAAs; BCKDH; MSUD; Maple syrup urine disease; Mutation.

Fig. 1

(a) The predicted 3D-structure of E1β heterotetramer modified from [17] together with the distribution of new missense mutations identified in this study. New missense mutations identified in E1α and E1β subunits are represented by brown and red spheres, respectively. E1α, E1β, E1α’ and E1β’ are shown in green, wheat, magenta and blue, respectively. The potassium, magnesium and chloride ions are presented in hot-pink, light blue and aquamarine, respectively. Thiamin diphosphates (ThDPs) are shown in yellow stick. The figure was generated with Pymol Version 1.7.4 [20]. (b) The predicted 3D-structure of human E2 subunit model together with the new missense mutation. New missense mutation identified is represented by yellow sphere. E2 subunit is shown in purple and CoA-enzyme in green stick. The figure was generated with Pymol Version 1.7.4 [20]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Structural illustration of the new missense mutations in E1b heterotetramer. a) New missense mutation in α subunit. b-h) New missense mutations in β subunit. Wild-type residue is in yellow sticks while mutated residue is in cyan sticks. Hydrogen bonds are denoted by black dotted lines. E1α, E1β, E1α’ and E1β’ are shown in green, wheat, magenta and blue, respectively. The potassium, magnesium and chloride ions are presented in hotpink, light blue and aquamarine, respectively. Thiamin diphosphates (ThDPs) are shown in yellow stick. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Structural analysis for new missense mutation in human E2 subunit model. The E2 subunit is shown in green transparency cartoon. Wild-type residue is in yellow sticks while mutated residue is in cyan sticks. CoA-enzyme (CoA) is shown in orange stick. Hydrogen bonds are denoted by black dotted lines. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)