Novel mutation in an Indian patient with Methylmalonic Acidemia, cblA type.
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ABSTRACT:
SUBMITTER: Girisha KM
PROVIDER: S-EPMC3656526 | biostudies-literature | 2012 Sep
REPOSITORIES: biostudies-literature
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Novel mutation in an Indian patient with Methylmalonic Acidemia, cblA type.
Girisha Katta Mohan KM Shrikiran Aroor A Bidchol Abdul Mueed AM Sakamoto Osamu O Gopinath Puthiya Mundyat PM Satyamoorthy Kapaettu K
Indian journal of human genetics 20120901 3
We report on a girl with methylmalonic acidemia, cblA type with a novel homozygous mutation and describe the clinical phenotype and response to therapy. ...[more]
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Project description:Deficiency or diminished activity of a cobalamin dependent enzyme methylmalonyl-CoA mutase causes inborn error of metabolism called methylmalonic acidemia (MMA). In this study we elucidated the spectrum of mutations in 21 Indian mut MMA patients by direct sequencing. Sequence analysis identified a total of 70 mutations in exon 2, 9, 11 and 12 of MUT gene. Out of which 26 mutations were predicted to be deleterious and rest were benign. The 23 novel mutations consist of four nonsense mutations (p.N6*, p.G539*, p.E609* and p.I671*), twelve missense mutations (p.K128I, p.N547T, p.D554Y, p.A558T, p.R559P, p.A631T, p.I647T, p.E656D, p.V657E, p.Q660H, p.K679N, and p.G696Y) and seven frame shift mutations (c.375_376insA, c.1642delA, c.1655delC, c.1825_1826insT, c.1957delGA, c.2014delA and c.2062_2063insGA). All of them are point mutations or micro rearrangements. Three of these mutations (p.K621N, p.G648D, p.G630E) have been previously reported; all of them are missense mutations. The mutations are distributed throughout the exon 2, 9, 11 and 12, 38.4 % mutation are located in exon 12.
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Project description:A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively. Recently he developed dystonic movements including orofacial dyskinesia. With advent of NGS, judicious use of NGS with Sanger sequencing can help identify causative possibly pathogenic mutations.
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Project description:BACKGROUND:Methylmalonic acidemia (MMA) is an autosomal recessive genetic disorder involving the metabolism of organic acids. METHODS:Here, we report the case of a patient who developed acute metabolic crisis after vaccination and was diagnosed with cblA type MMA after hospitalization. RESULTS:Further examination revealed a homozygous pathogenic variant in the MMAA gene that caused the disease in the patient but did not conform to Mendelian inheritance. Using chromosomal microarray analysis, maternal uniparental disomy (UPD) was found on chromosome 4q26-q35.2 of the patient. The MMAA gene of the patient was inherited only from the mother and carried the same pathogenic variant on both alleles of chromosome 4. MMAA gene expression levels in whole blood were detected by real-time PCR. CONCLUSION:The nonsense pathogenic variant, NM_172250.2:c.742C>T (p.Gln248*), carried by the patient leads to a premature termination of transcription of the gene, thereby resulting in partial loss of protein function while retaining some others. Segmental UPD 4 is rare, and to our knowledge, has not been reported previously.
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Project description:OBJECTIVE:To construct a W203X-mutant mouse model of cblC type methylmalonic acidemia based on the CRISPR/Cas9 technology. METHODS:At first, BLAST was used to compare the conservative nature of the cblC gene and protein sequences in humans and mice, and then, the CRISPR/Cas9 technology was used for microinjection of mouse fertilized eggs to obtain heterozygous F1 mice. Hybridization was performed for these mice to obtain homozygous W203X-mutant mice. The blood level of the metabolite propionyl carnitine (C3) was measured for homozygous mutant mice, heterozygous littermates, and wild-type mice. RESULTS:The gene and protein sequences of MMACHC, the pathogenic gene for cblC type methylmalonic acidemia, were highly conserved in humans and mice. The homozygous W203X-mutant mice were successfully obtained by the CRISPR/Cas9 technology, and there was a significant increase in C3 in these mice at 24 hours after birth (P<0.001). CONCLUSIONS:A W203X-mutant mouse model of cblC type methylmalonic acidemia is successfully constructed by the CRISPR/Cas9 technology.
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