Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency is an autosomal recessive disorder affecting the leucine catabolic pathway and ketone body synthesis, and is clinically characterized by metabolic crises with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. In the...

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Published in:International journal of molecular medicine 2015-06, Vol.35 (6), p.1554-1560
Main Authors: AOYAMA, YUKA, YAMAMOTO, TOSHIYUKI, SAKAGUCHI, NAOMI, ISHIGE, MIKA, TANAKA, TOJU, ICHIHARA, TOMOKO, OHARA, KATSUAKI, KOUZAN, HIROKO, KINOSADA, YASUTOMI, FUKAO, TOSHIYUKI
Format: Article
Language:English
Subjects:
Age
Alu element
Chromosomes
Deficiency diseases
Deoxyribonucleic acid
DNA
Genetic aspects
Genetic research
Genetic susceptibility
Hypoglycemia
microarray
mitochondrial 3-hydroxy-3-methylglutaryl CoA lyase
multiplex ligation-dependent probe amplification
Mutation
Patients
Risk factors
uniparental disomy
Urine
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Summary:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency is an autosomal recessive disorder affecting the leucine catabolic pathway and ketone body synthesis, and is clinically characterized by metabolic crises with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. In the present study, we initially used PCR with genomic followed by direct sequencing to investigate the molecular genetic basis of HMGCL deficiency in two patients clinically diagnosed with the condition. Although we identified a mutation in each patient, the inheritance patterns of these mutations were not consistent with disease causation. Therefore, we investigated HMGCL using multiplex ligation-dependent probe amplification (MLPA) to determine the copy numbers of all exons. A heterozygous deletion that included exons 2-4 was identified in one of the patients. MLPA revealed that the other patient had two copies for all HMGCL exons. Paternal uniparental isodisomy of chromosome 1 was confirmed in this patient by microarray analysis. These findings indicate that MLPA is useful for the identification of genomic aberrations and mutations other than small-scale nucleotide alterations. To the best of our knowledge, this is the first study describing HMGCL deficiency caused by uniparental disomy.
ISSN:1107-3756
1791-244X
DOI:10.3892/ijmm.2015.2184