Abstract
Maple syrup urine disease is the primary aminoacidopathy affecting branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by the deficiency of an enzyme named branched-chained α-keto acid dehydrogenase (BCKD), which consist of four subunits (E1α, E1β, E2, and E3), and encoded by BCKDHA, BCKDHB, DBT, and DLD gene respectively. BCKD is the main enzyme in the catabolism pathway of BCAAs. Hight rate of autosomal recessive disorders is expected from consanguineous populations like Iran. In this study, we selected two sets of STR markers linked to the four genes, that mutation in which can result in MSUD disease. The patients who had a homozygous haplotype for selected markers of the genes were sequenced. In current survey, we summarized our recent molecular genetic findings to illustrate the mutation spectrum of MSUD in our country. Ten novel mutations including c.484 A > G, c.834_836dup CAC, c.357del T, and c. (343 + 1_344–1) _ (742 + 1_743–1)del in BCKDHB, c.355–356 ins 7 nt ACAAGGA, and c.703del T in BCKDHA, and c.363delCT/c.1238 T > C, c. (433 + 1_434–1) _ (939 + 1_940–1)del, c.1174 A > C, and c.85_86ins AACG have been found in DBT gene. Additionally, structural models of MSUD mutations have been performed to predict the pathogenicity of the newly identified variants.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abiri M et al (2016) Identification of six novel mutations in Iranian patients with maple syrup urine disease and their in silico analysis. Mutat Res 786:34–40. https://doi.org/10.1016/j.mrfmmm.2016.01.005
Abiri M et al (2017) In silico analysis of novel mutations in maple syrup urine disease patients from Iran. Metab Brain Dis 32:105–113. https://doi.org/10.1007/s11011-016-9867-1
Adzhubei IA et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. https://doi.org/10.1038/nmeth0410-248
Ævarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WGJ (2000) Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure 8(3):277–291
Al-Shamsi A, Baker A, Dhawan A, Hertecant J (2016) Acute Metabolic Crises in Maple Syrup Urine Disease After Liver Transplantation from a Related Heterozygous Living Donor. JIMD Rep 30:59–62. https://doi.org/10.1007/8904_2016_532
Benson G (1999) Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 27:573–580
Blackburn PR et al (2017) Maple syrup urine disease: mechanisms and management. Appl Clin Genet 10:57–66. https://doi.org/10.2147/tacg.s125962
Burrage LC, Nagamani SC, Campeau PM, Lee BH (2014) Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet 23:R1–R8. https://doi.org/10.1093/hmg/ddu123
den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12. https://doi.org/10.1002/(sici)1098-1004(200001)15:1<7::aid-humu4>3.0.co;2-n
Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67. https://doi.org/10.1093/nar/gkp215
Eswar N et al. (2007) Comparative protein structure modeling using MODELLER Current protocols in protein science Chapter 2:Unit 2.9 https://doi.org/10.1002/0471140864.ps0209s50
Flaschker N, Feyen O, Fend S, Simon E, Schadewaldt P, Wendel U (2007) Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis 30:903–909. https://doi.org/10.1007/s10545-007-0579-x
Gorzelany K et al (2009) Molecular genetics of maple syrup urine disease in the Turkish population. Turk J Pediatr 51:97-102
Harris RA, Joshi M, Jeoung NH (2004) Mechanisms responsible for regulation of branched-chain amino acid catabolism. Biochemical and Biophysical Research Communications 313:391–396
Hayashida Y, Mitsubuchi H, Indo Y, Ohta K, Endo F, Wada Y, Matsuda I (1994) Deficiency of the E1 beta subunit in the branched-chain alpha-keto acid dehydrogenase complex due to a single base substitution of the intron 5, resulting in two alternatively spliced mRNAs in a patient with maple syrup urine disease. Biochim Biophys Acta 1225:317–325
Henneke M, Flaschker N, Helbling C, Muller M, Schadewaldt P, Gartner J, Wendel U (2003) Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Hum Mutat 22:417. https://doi.org/10.1002/humu.9187
Hu J, Ng PC (2012) Predicting the effects of frameshifting indels. Genome Biol 13:R9. https://doi.org/10.1186/gb-2012-13-2-r9
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(33–38):27–38
Jung Min K et al (2014) Identification of two novel BCKDHB mutations in Korean siblings with maple syrup urine disease showing mild clinical presentation. J Genet Med 11:22–26
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. https://doi.org/10.1038/nprot.2009.86
Li X et al (2018) Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease. Metab Brain Dis 33:741–751. https://doi.org/10.1007/s11011-017-0168-0
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Miryounesi M, Ghafouri-Fard S, Goodarzi H, Fardaei M (2015) A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD). J Pediatr Endocrinol Metab 28:673–675. https://doi.org/10.1515/jpem-2014-0341
Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI (2002) Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 109:999–1008. https://doi.org/10.1542/peds.109.6.999
Narayanan MP, Menon KN, Vasudevan DM (2013) Analysis of gene mutations among south Indian patients with maple syrup urine disease: identification of four novel mutations. Indian J Biochem Biophys 50:442–446
Nellis MM, Kasinski A, Carlson M, Allen R, Schaefer AM, Schwartz EM, Danner DJ (2003) Relationship of causative genetic mutations in maple syrup urine disease with their clinical expression. Mol Genet Metab 80:189–195
Phillips JC et al (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802. https://doi.org/10.1002/jcc.20289
Ribas GS, Vargas CR, Wajner M (2014) L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 533:469–476. https://doi.org/10.1016/j.gene.2013.10.017
Saadat M, Ansari-Lari M, Farhud DD (2004) Consanguineous marriage in Iran. Ann Hum Biol 31:263–269. https://doi.org/10.1080/03014460310001652211
Safdarian E, Galehdari H, Jafarian V, Shafee M, Shariati G, Hamid M, Saberi A (2016) A novel mutation in the BCKDHB gene causes in an Iranian child classic maple syrup urine disease. Zahedan J Res Med Sci 18:e3399. https://doi.org/10.17795/zjrms-3399
Shaw V (2014) Clinical paediatric dietetics, Blackwell science. John Wiley & Sons, London
Strauss KA, Puffenberger EG, Morton DH (2012) One community's effort to control genetic disease. Am J Public Health 102:1300–1306. https://doi.org/10.2105/ajph.2011.300569
Teeuw ME, Loukili G, Bartels EA, ten Kate LP, Cornel MC, Henneman L (2014) Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society. Eur J Hum Genet 22:452–457. https://doi.org/10.1038/ejhg.2013.167
Word JM, Lovell SC, Richardson JS, Richardson DC (1999) Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J Mol Biol 285:1735–1747. https://doi.org/10.1006/jmbi.1998.2401
Wynn RM, Davie JR, Chuang JL, Cote CD, Chuang DT (1998) Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease. J Biol Chem 273:13110–13118
Yang N et al (2012) Analysis of gene mutations in Chinese patients with maple syrup urine disease. Mol Genet Metab 106:412–418. https://doi.org/10.1016/j.ymgme.2012.05.023
Yoshino M et al (1999) Management of acute metabolic decompensation in maple syrup urine disease: a multi-center study. Pediatrics international : official journal of the Japan Pediatric Society 41:132–137
Zeltner NA, Huemer M, Baumgartner MR, Landolt MA (2014) Quality of life, psychological adjustment, and adaptive functioning of patients with intoxication-type inborn errors of metabolism - a systematic review. Orphanet Journal of Rare Diseases 9:159. https://doi.org/10.1186/s13023-014-0159-8
Zeynalzadeh M et al (2018) Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease. J Pediatr Endocrinol Metab 31:205–212. https://doi.org/10.1515/jpem-2017-0305
Acknowledgments
We thank the patients and their families for their cooperation in this study.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declared no potential conflict of interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 17 kb)
Rights and permissions
About this article
Cite this article
Abiri, M., Saei, H., Eghbali, M. et al. Maple syrup urine disease mutation spectrum in a cohort of 40 consanguineous patients and insilico analysis of novel mutations. Metab Brain Dis 34, 1145–1156 (2019). https://doi.org/10.1007/s11011-019-00435-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-019-00435-y