title: Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients.
abstract: Maple syrup urine disease (MSUD) is caused by mutations in genes BCKDHA, BCKDHB, DBT encoding E1α, E1β, and E2 subunits of enzyme complex, branched-chain alpha-ketoacid dehydrogenase (BCKDH). BCKDH participates in catabolism of branched-chain amino acids (BCAAs) - leucine, isoleucine and valine in the energy production pathway. Deficiency or defect in the enzyme complex causes accumulation of BCAAs and keto-acids leading to toxicity. Twenty-four patients with MSUD were enrolled in the study for molecular characterization and genotype-phenotype correlation. Molecular studies were carried out by sequencing of the 3 genes by Sanger method. Bioinformatics tools were employed to classify novel variations into pathogenic or benign. The predicted effects of novel changes on protein structure were elucidated by 3D modeling. Mutations were detected in 22 of 24 patients (11, 7 and 4 in BCKDHB, BCKDHA and DBT genes, respectively). Twenty mutations including 11 novel mutations were identified. Protein modeling in novel mutations showed alteration of structure and function of these subunits. Mutations, c.1065 delT (BCKDHB gene) and c.939G > C (DBT gene) were noted to be recurrent, identified in 6 of 22 alleles and 5 of 8 alleles, respectively. Two-third patients were of neonatal classical phenotype (16 of 24). BCKDHB gene mutations were present in 10 of these 16 patients. Prenatal diagnoses were performed in 4 families. Consanguinity was noted in 37.5% families. Although no obvious genotype-phenotype correlation could be found in our study, most cases with mutation in BCKDHB gene presented in neonatal period. Large number of novel mutations underlines the heterogeneity and distinctness of gene pool from India.
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India; Amity Institute of Biotechnology, Amity University, Noida, U.P., India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India. Electronic address: bijarnia@gmail.com.
authors.forename: Sunita
authors.initials: S
authors.lastname: Bijarnia-Mahay
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: Renu
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kohli
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: Ratna
authors.initials: R
authors.lastname: Dua-Puri
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Verma
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: E
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Department of Health Science, Faculty of Medical Sciences, University of Fukui, Matsuoka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shigematsu
authors.affiliation: Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Amity Institute of Biotechnology, Amity University, Noida, U.P., India.
authors.forename: Roumi
authors.initials: R
authors.lastname: Deb
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India.
authors.forename: Ishwar Chander
authors.initials: IC
authors.lastname: Verma
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D002675:Child, Preschool; D019295:Computational Biology; D003241:Consanguinity; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008375:Maple Syrup Urine Disease / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D011296:Prenatal Diagnosis; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
chemical_list: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
keywords: BCKDHA; BCKDHB; DBT; Genetics; Genotype–phenotype; Indian; Maple syrup urine disease; Modeling; Mutation; Prenatal diagnosis