1. Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia

Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia

F. Keyfi 1, 2 Mohammad Reza Abbaszadegan, PhD 1, 2 Prof. Arndt Rolfs, MD 3, 4 Slobodanka Orolicki, MD PhD 3 Morteza Moghaddassian 1 Prof. Abdol Reza Varasteh, MD 1, 2
1 Mashhad University 2 Pardis Clinical and Genetic Laboratory, Mashhad 3 CENTOGENE AG 4 University of Rostock
July 28, 2016

Keyfi et al. Cellular & Molecular Biology Letters (2016) 21:4

Abstract:

Background
Adenosylcobalamin (vitamin B12) is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this enzyme are a cause of methylmalonic acidemia (MMA). Methylmalonic acidemia, cblA type, is an inborn error of vitamin B12 metabolism that occurs due to mutations in the MMAA gene. MMAA encodes the enzyme which is involved in translocation of cobalamin into the mitochondria.

Methods
One family with two MMA-affected children, one unaffected child, and their parents were studied. The two affected children were diagnosed by urine organic acid analysis using gas chromatography-mass spectrometry. MMAA was analyzed by PCR and sequencing of its coding region.

Results
Ahomozygousdeletioninexon4ofMMAA,c.674delA,wasfoundinboth affected children. This delet ion causes a nucleotide frame shift resulting in a change from asparagine to methionine at amino acid 225 (p.N225M) and a truncated protein which loses the ArgK conserved domain site. mRNA expression analysis of MMAA confirmed these results.

Conclusions
We demonstrate that the deletion in exon 4 of the MMAA gene (c.674 delA) is a pathogenic allele via a nucleotide frame shift resulting in a stop codon and termination of protein synthesis 38 nucleotides (12 amino acids) downstream of the deletion.