In silico analysis of novel mutations in maple syrup urine disease patients from Iran

Abstract

Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1α, E1β, E2 and E3 subunits of branched-chain α-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.

Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity

“…However, Quental et al [ 6 ], in a study with 30 Portuguese patients, found 17 mutations with no difference in the frequency of these genes, with six in the BCKDHA gene, five in the BCKDHB gene, and six in the DBT gene. A study published by Abiri et al [ 27 ] investigating 20 Iranian families of MSUD patients, six patients demonstrated homozygous haplotype for the BCKDHA gene, nine for the BCKDHB gene, and two for the DBT gene. Gupta et al [ 28 ], studying 24 unrelated Indian patients, found 20 mutations in 22 of the patients, with 11 novel mutations—four in the BCKDHA gene, six in the BCKDHB gene, with a novel mutation identified in the DBT gene.…”

Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

“…However, Quental et al (5), in a study with 30 Portuguese patients, found 17 mutations with no difference in the frequency of these genes, with six in the BCKDHA gene, ve in the BCKDHB gene, and six in the DBT gene. A study published by Abiri et al (24) investigating 20 Iranian families of MSUD patients, six patients demonstrated homozygous haplotype for the BCKDHA gene, nine for the BCKDHB gene, and two for the DBT gene. Gupta et al (26), studying 24 unrelated Indian patients, found 20 mutations in 22 of the patients, with 11 novel mutations -four in the BCKDHA gene, six in the BCKDHB gene, with a novel mutation identi ed in the DBT gene.…”

Maple Syrup Urine Disease in Brazilian Patients: Variants and Clinical Phenotype Heterogeneity

“…However, Quental et al 5, in a study with 30 Portuguese patients, found 17 mutations with no difference in the frequency of these genes, with six in the BCKDHA gene, ve in the BCKDHB gene, and six in the DBT gene. A study published by Abiri et al (24) investigating 20 Iranian families of MSUD patients, six patients demonstrated homozygous haplotype for the BCKDHA gene, nine for the BCKDHB gene, and two for the DBT gene. Gupta et al (26), studying 24 unrelated Indian patients, found 20 mutations in 22 of the patients, with 11 novel mutations -four in the BCKDHA gene, six in the BCKDHB gene, with a novel mutation identi ed in the DBT gene.…”