Identification and characterization of IVD gene mutations in Korean patients with isovaleric acidemia

¹Yong-Wha Lee, ²Dong Hwan Lee, ³Jerry Vockley, ⁴Nam-Doo Kim, ¹You Kyoung Lee, ⁵Chang-Seok Ki
¹Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang Univerisity College of Medicine, Bucheon, South Korea, ²Department of Pediatrics, Soonchunhyang Univerisity College of Medicine, Seoul, South Korea, ³Department of Pediatrics, University of Pittsburgh School of Medicine, The Children's Hospital of Pittsburgh, Pittsburgh, PA, United States of America, ⁴R and D Center, Equispharm Co., Ltd, Ansan, South Korea, ⁵Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism that is caused by isovaleryl-CoA dehydrogenase (IVD) deficiency. Recent application of tandem mass spectrometry for newborn screening has allowed a significant expansion of the recognition of individuals with IVD deficiency. Although many patients have been reported worldwide, there is no genetically confirmed patient in Korea. In the present study, we characterized the IVD mutations of seven Korean patients from six unrelated families with IVA. Bi-directional sequencing analysis identified two novel variations affecting consensus splice sites (c.144+1G>T in intron 1 and c.457-3_2CA>GG in intron 4) and three novel variations altering coding sequences (c.149G>T; Arg21Leu, c.832A>G; Ser249Gly, and c.1135T>G; Phe350Val). Five patients from four families were compound heterozygotes while two unrelated patients were homozygous for the c.457-3_2CA>GG variation. Reverse-transcription polymerase chain reaction confirmed that both intronic variations cause aberrant splicing. Furthermore, enzyme assay and Western blot analysis showed that the expression levels of mutant proteins were significantly decreased (less than 10.0% of control) and enzyme activities of all the mutant forms showed null status. These results confirm that Korean patients with IVA were also caused by the mutations in the IVD gene but the mutation spectrum is different from other ethnicities.