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

Aoyama,Yuka; Yamamoto,Toshiyuki; Sakaguchi,Naomi; Ishige,Mika; Tanaka,Toju; Ichihara,Tomoko; Ohara,Katsuaki; Kouzan,Hiroko; Kinosada,Yasutomi; Fukao,Toshiyuki

doi:10.3892/ijmm.2015.2184

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

Authors:
- Yuka Aoyama
- Toshiyuki Yamamoto
- Naomi Sakaguchi
- Mika Ishige
- Toju Tanaka
- Tomoko Ichihara
- Katsuaki Ohara
- Hiroko Kouzan
- Yasutomi Kinosada
- Toshiyuki Fukao
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Affiliations: Medical Information Sciences Division, United Graduate School of Drug Discovery and Medical information Sciences, Gifu University, Gifu 501-1194, Japan, Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo 162‑8666, Japan, Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501‑1194, Japan, Department of Pediatrics, Nihon University School of Medicine, Sapporo, Hokkaido 063‑0005, Japan, Department of Pediatrics and Clinical Research, NHO Hokkaido Medical Center, Sapporo, Hokkaido 063‑0005, Japan, Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu, Kagawa 760-0017, Japan
Published online on: April 14, 2015 https://doi.org/10.3892/ijmm.2015.2184
Pages: 1554-1560
Copyright: © Aoyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

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.

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1	Wang SP, Robert MF, Gibson KM, Wanders RJ and Mitchell GA: 3-Hydroxy-3-methylglutaryl CoA lyase (HL): mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients. Genomics. 33:99–104. 1996. View Article : Google Scholar : PubMed/NCBI
2	Fukao T, Mitchell G, Sass JO, Hori T, Orii K and Aoyama Y: Ketone body metabolism and its defects. J Inherit Metab Dis. 37:541–551. 2014. View Article : Google Scholar : PubMed/NCBI
3	Muroi J, Yorifuji T, Uematsu A, Shigematsu Y, Onigata K, Maruyama H, Nobutoki T, Kitamura A and Nakahata T: Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. Hum Genet. 107:320–326. 2000. View Article : Google Scholar : PubMed/NCBI
4	Sen SK, Han K, Wang J, Lee J, Wang H, Callinan PA, Dyer M, Cordaux R, Liang P and Batzer MA: Human genomic deletions mediated by recombination between Alu elements. Am J Hum Genet. 79:41–53. 2006. View Article : Google Scholar : PubMed/NCBI
5	Fukao T, Aoyama Y, Murase K, Hori T, Harijan RK, Wierenga RK, Boneh A and Kondo N: Development of MLPA for human ACAT1 gene and identification of a heterozygous Alu-mediated deletion of exons 3 and 4 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab. 110:184–187. 2013. View Article : Google Scholar : PubMed/NCBI
6	Fukao T, Zhang G, Rolland MO, Zabot MT, Guffon N, Aoki Y and Kondo N: Identification of an Alu-mediated tandem duplication of exons 8 and 9 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab. 92:375–378. 2007. View Article : Google Scholar : PubMed/NCBI
7	Zhang G, Fukao T, Sakurai S, Yamada K, Michael Gibson K and Kondo N: Identification of Alu-mediated, large deletion-spanning exons 2–4 in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency. Mol Genet Metab. 89:222–226. 2006. View Article : Google Scholar : PubMed/NCBI
8	Gatta V1, Scarciolla O, Gaspari AR, Palka C, De Angelis MV, Di Muzio A, Guanciali-Franchi P, Calabrese G, Uncini A and Stuppia L: Identification of deletions and duplications of the DMD gene in affected males and carrier females by multiple ligation probe amplification (MLPA). Hum Genet. 117:92–98. 2005. View Article : Google Scholar : PubMed/NCBI
9	Janssen B, Hartmann C, Scholz V, Jauch A and Zschocke J: MLPA analysis for the detection of deletions, duplications and complex rearrangements in the dystrophin gene: potential and pitfalls. Neurogenetics. 6:29–35. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lalic T, Vossen RH, Coffa J, Schouten JP, Guc-Scekic M, Radivojevic D, Djurisic M, Breuning MH, White SJ and den Dunnen JT: Deletion and duplication screening in the DMD gene using MLPA. Eur J Hum Genet. 13:1231–1234. 2005. View Article : Google Scholar : PubMed/NCBI
11	Tomoko T, Takanori S, Kazumi O, et al: A case of 3-Hydroxy-3-methylglutaryl CoA lyase deficiency. J Jpn Pediatr Soc. 112:1249–1254. 2008.In Japanese.
12	Zhi J and Hatchwell E: Human MLPA Probe Design (H-MAPD): a probe design tool for both electrophoresis-based and bead-coupled human multiplex ligation-dependent probe amplification assays. BMC Genomics. 9:4072008. View Article : Google Scholar : PubMed/NCBI
13	Ledbetter DH and Engel E: Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Hum Mol Genet. 4:Spec No. 1757–1764. 1995.PubMed/NCBI
14	Riveiro-Alvarez R, Valverde D, Lorda-Sanchez I, Trujillo-Tiebas MJ, Cantalapiedra D, Vallespin E, Aguirre-Lamban J, Ramos C and Ayuso C: Partial paternal uniparental disomy (UPD) of chromosome 1 in a patient with Stargardt disease. Mol Vis. 13:96–101. 2007.PubMed/NCBI
15	Shimojima K, Tanaka R, Shimada S, Sangu N, Nakayama J, Iwasaki N and Yamamoto T: A novel homozygous mutation of GJC2 derived from maternal uniparental disomy in a female patient with Pelizaeus-Merzbacher-like disease. J Neurol Sci. 330:123–126. 2013. View Article : Google Scholar : PubMed/NCBI
16	Wassink TH, Losh M, Frantz RS, Vieland VJ, Goedken R, Piven J and Sheffield VC: A case of autism and uniparental disomy of chromosome 1. Hum Genet. 117:200–206. 2005. View Article : Google Scholar : PubMed/NCBI
17	Zeng WQ, Gao H, Brueton L, Hutchin T, Gray G, Chakrapani A, Olpin S and Shih VE: Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1. Am J Med Genet A. 140:1004–1009. 2006. View Article : Google Scholar : PubMed/NCBI
18	Nimmo G, Monsonego S, Descartes M, Franklin J, Steinberg S and Braverman N: Rhizomelic chrondrodysplasia punctata type 2 resulting from paternal isodisomy of chromosome 1. Am J Med Genet A. 152A:1812–1817. 2010. View Article : Google Scholar : PubMed/NCBI
19	Roberts JL1, Buckley RH, Luo B, Pei J, Lapidus A, Peri S, Wei Q, Shin J, Parrott RE and Dunbrack RL Jr: CD45-deficient severe combined immunodeficiency caused by uniparental disomy. Proc Natl Acad Sci USA. 109:10456–10461. 2012. View Article : Google Scholar : PubMed/NCBI
20	Le Beyec J, Cugnet-Anceau C, Pépin D, Alili R, Cotillard A, Lacorte JM, Basdevant A and Laville Mand Clément K: Homozygous leptin receptor mutation due to uniparental disomy of chromosome 1: response to bariatric surgery. J Clin Endocrinol Metab. 98:E397–E402. 2013. View Article : Google Scholar : PubMed/NCBI