Functional Analysis of A Novel Splicing Mutation in The Mutase Gene of Two Unrelated Pedigrees

Document Type : Original Article


1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

2 Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;4Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran Univers


Methylmalonic acidura (MMA) is a rare autosomal recessive inborn error of metabolism. In this study we present a novel nucleotide change in the mutase (MUT) gene of two unrelated Iranian pedigrees and introduce the methods used for its functional analysis.
Materials and Methods
Two probands with definite diagnosis of MMA and a common novel variant in the MUT were included in a descriptive study. Bioinformatic prediction of the splicing variant was done with different prediction servers. Reverse transcriptionpolymerase chain reaction (RT-PCR) was done for splicing analysis and the products were analyzed by sequencing.
The included index patients showed elevated levels of propionylcarnitine (C3). Urine organic acid analysis confirmed the diagnosis of MMA, and screening for mutations in the MUT revealed a novel C to G variation at the 3´ splice acceptor site in intron 12. In silico analysis suggested the change as a mutation in a conserved sequence. The splicing analysis showed that the C to G nucleotide change at position -3 in the acceptor splice site can lead to retention of the intron 12 sequence.
This is the first report of a mutation at the position -3 in the MUT intron 12 (c.2125-3C>G). The results suggest that the identified variation can be associated with the typical clinical manifestations of MMA.