Molecular basis of various forms of maple syrup urine disease in Chilean patients.
branched-chain amino acids
inborn errors of metabolism
isoleucine
leucine
maple syrup urine disease
valine
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
05
01
2021
received:
10
07
2020
accepted:
13
01
2021
pubmed:
7
5
2021
medline:
20
1
2022
entrez:
6
5
2021
Statut:
ppublish
Résumé
Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1β, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients. This manuscript describes a cross-sectional study of 18 MSUD patients carried out using PCR and DNA sequencing. Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients. If MSUD is diagnosed earlier, with a newborn screening approach, it might be possible to establish genotype-phenotype relationships more efficiently.
Sections du résumé
BACKGROUND
Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1β, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients.
METHODS
This manuscript describes a cross-sectional study of 18 MSUD patients carried out using PCR and DNA sequencing.
RESULTS
Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients.
CONCLUSION
If MSUD is diagnosed earlier, with a newborn screening approach, it might be possible to establish genotype-phenotype relationships more efficiently.
Identifiants
pubmed: 33955723
doi: 10.1002/mgg3.1616
pmc: PMC8172190
doi:
Substances chimiques
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
EC 1.2.4.4
Dihydrolipoamide Dehydrogenase
EC 1.8.1.4
Acyltransferases
EC 2.3.-
dihydrolipoamide acyltransferase
EC 2.3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1616Informations de copyright
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
Références
Genet Med. 2014 Aug;16(8):594-600
pubmed: 24603436
Am J Hum Genet. 2007 Apr;80(4):588-604
pubmed: 17357067
J Biol Chem. 2004 Apr 23;279(17):17792-800
pubmed: 14742428
J Nutr. 2005 Jun;135(6 Suppl):1565S-70S
pubmed: 15930470
Hum Mutat. 2000;15(1):7-12
pubmed: 10612815
J Pediatr Gastroenterol Nutr. 2014 Nov;59(5):636-9
pubmed: 24979318
Eur J Med Genet. 2015 Nov;58(11):617-23
pubmed: 26453840
Hum Mutat. 2000;15(1):57-61
pubmed: 10612823
Clin Chem. 1999 Oct;45(10):1734-40
pubmed: 10508118
Pediatrics. 2002 Jun;109(6):999-1008
pubmed: 12042535
Hum Mutat. 2006 Jul;27(7):715
pubmed: 16786533
Hum Genet. 2014 Jan;133(1):1-9
pubmed: 24077912
Braz J Med Biol Res. 2014 Jun;47(6):522-6
pubmed: 24770567
J Med Genet. 1994 Sep;31(9):702-6
pubmed: 7815439
Eur J Med Genet. 2020 Jun;63(6):103901
pubmed: 32151765
Mol Genet Metab. 2010 Aug;100(4):385-7
pubmed: 20466570
Pediatr Int. 1999 Apr;41(2):132-7
pubmed: 10221014
Bioinformatics. 2009 Nov 1;25(21):2744-50
pubmed: 19734154
Genome Res. 2001 May;11(5):863-74
pubmed: 11337480
Nat Methods. 2014 Apr;11(4):361-2
pubmed: 24681721