J Pediatr Genet 2018; 07(03): 097-102
DOI: 10.1055/s-0038-1667036
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Identification of Two Novel Mutations in Aminomethyltransferase Gene in Cases of Glycine Encephalopathy

Akella Radha Rama Devi
1   Department of Biochemical Genetics, Sandor Lifesciences Pvt. Ltd., Banjara Hills, Hyderabad, Telangana, India
2   Neuro-Metabolic Unit, Rainbow Children's Hospital, Hyderabad, Telangana, India
,
Lokesh Lingappa
2   Neuro-Metabolic Unit, Rainbow Children's Hospital, Hyderabad, Telangana, India
,
Shaik Mohammad Naushad
1   Department of Biochemical Genetics, Sandor Lifesciences Pvt. Ltd., Banjara Hills, Hyderabad, Telangana, India
› Author Affiliations
Further Information

Publication History

10 May 2018

04 June 2018

Publication Date:
06 July 2018 (online)

Abstract

In this study, we report three cases of nonketotic hyperglycinemia (NKHG) diagnosed biochemically and molecularly. Clinical exome analysis in two families revealed two novel mutations in the aminomethyltransferase (AMT) gene, that is, c.14_15insT (p.Ser6LysfsTer22) and c.259–2A > T, both of them adversely affecting the protein. This is the first report of AMT gene mutations in NKHG from India. Prenatal diagnosis in the first family showed an unaffected fetus in the third pregnancy. The role of AMT protein is pivotal for the synthesis of 5,10-methylene tetrahydrofolate, the first metabolite in one-carbon metabolism that regulates DNA synthesis, repair, and methylation.

Supplementary Material

 
  • References

  • 1 Kure S, Kato K, Dinopoulos A. , et al. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. Hum Mutat 2006; 27 (04) 343-352
  • 2 Kikuchi G, Motokawa Y, Yoshida T, Hiraga K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad, Ser B, Phys Biol Sci 2008; 84 (07) 246-263
  • 3 Kure S, Takayanagi M, Narisawa K, Tada K, Leisti J. Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia. J Clin Invest 1992; 90 (01) 160-164
  • 4 Rezvani I, Melvin JJ. Defects in metabolism of amino acids. In: Kliegman RM, Stanton BF, St Geme J, Behrman RE. , eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Elsevier; 2011: 439e40
  • 5 Hove JV, Coughlin C, Scharer G. Glycine Encephalopathy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE. , eds. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2018
  • 6 Hennermann JB, Berger JM, Grieben U, Scharer G, Van Hove JL. Prediction of long-term outcome in glycine encephalopathy: a clinical survey. J Inherit Metab Dis 2012; 35 (02) 253-261
  • 7 Tada K, Kure S. Nonketotic hyperglycinemia: pathophysiological studies. Proc Japan Acad Ser B 2005; 81: 411
  • 8 von Wendt L, Hirvasniemi A, Similä S. Nonketotic hyperglycinemia. A genetic study of 13 Finnish families. Clin Genet 1979; 15 (05) 411-417
  • 9 Abecasis GR, Auton A, Brooks LD. , et al; 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491 (7422): 56-65
  • 10 Lek M, Karczewski KJ, Minikel EV. , et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536 (7616): 285-291
  • 11 Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11 (04) 361-362
  • 12 ClinVar. Available at: https://www.ncbi.nlm.nih.gov/clinvar/
  • 13 The Human Gene Mutation Database (HGMD) at the Institute of Medical Genetics in Cardiff. Available at: http://www.hgmd. cf.ac.uk/ac/gene.phpgeneZGLDC . Accessed October 11, 2014
  • 14 Bhamkar RP, Colaco P. Neonatal nonketotic hyperglycinemia. Indian J Pediatr 2007; 74 (12) 1124-1126
  • 15 Love JM, Prosser D, Love DR, Chintakindi KP, Dalal AB, Aggarwal S. A novel glycine decarboxylase gene mutation in an Indian family with nonketotic hyperglycinemia. J Child Neurol 2014; 29 (01) 122-127
  • 16 Coughlin II CR, Swanson MA, Kronquist K. , et al. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. Genet Med 2017; 19 (01) 104-111
  • 17 Nanao K, Takada G, Takahashi E. , et al. Structure and chromosomal localization of the aminomethyltransferase gene (AMT). Genomics 1994; 19 (01) 27-30
  • 18 Hayasaka K, Nanao K, Takada G, Okamura-Ikeda K, Motokawa Y. Isolation and sequence determination of cDNA encoding human T-protein of the glycine cleavage system. Biochem Biophys Res Commun 1993; 192 (02) 766-771
  • 19 Swanson MA, Coughlin Jr CR, Scharer GH. , et al. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Ann Neurol 2015; 78 (04) 606-618