Identification of a Novel Splicing Mutation in the ARSA Gene in a Patient with Late-infantile Form of Metachromatic Leukodystrophy
0
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Metachromatic leukodystrophy (MLD; MIM 250100), a severe neurodegenerative disorder inherited as an autosomal recessive trait, is caused by mutations in the arylsulfatase A (ARSA) gene. Although several germ line ARSA mutations have been identified in patients with MLD of various ethnic backgrounds elsewhere in the world, no genetically confirmed cases of MLD have been reported in Korea. Recently, we identified a mutation in the ARSA gene of a Korean male with MLD. A male infant with late-infantile form of MLD had been admitted to our hospital for further examination. His neuromuscular symptoms, which included inability to walk at the age of 12 months, gradually worsened, even after allograft bone marrow transplantation; he died at the age of 9 yr. His elder brother had also been diagnosed with MLD. To confirm the presence of a genetic abnormality, all the coding exons of the ARSA gene and the flanking introns were amplified by PCR. A molecular analysis of the ARSA gene revealed both a novel heterozygous splicing mutation (c.1101+1G>T) in intron 6 and a heterozygous missense mutation in exon 2 (c.296G>A; Gly99Asp). The patient’s elder brother who had MLD is believed to have had the same mutation, which may be correlated with a rapidly deteriorating clinical course. This study identified a novel mutation in the ARSA gene, related to a late-infantile form of MLD with a lethal clinical course and suggested that molecular diagnosis of patients may be useful in early diagnosis and for deciding intervention measures for their family members. (Korean J Lab Med 2010;30:516-20)
Abstract
Metachromatic leukodystrophy (MLD; MIM 250100), a severe neurodegenerative disorder inherited as an autosomal recessive trait, is caused by mutations in the arylsulfatase A (ARSA) gene. Although several germ line ARSA mutations have been identified in patients with MLD of various ethnic backgrounds elsewhere in the world, no genetically confirmed cases of MLD have been reported in Korea. Recently, we identified a mutation in the ARSA gene of a Korean male with MLD. A male infant with late-infantile form of MLD had been admitted to our hospital for further examination. His neuromuscular symptoms, which included inability to walk at the age of 12 months, gradually worsened, even after allograft bone marrow transplantation; he died at the age of 9 yr. His elder brother had also been diagnosed with MLD. To confirm the presence of a genetic abnormality, all the coding exons of the ARSA gene and the flanking introns were amplified by PCR. A molecular analysis of the ARSA gene revealed both a novel heterozygous splicing mutation (c.1101+1G>T) in intron 6 and a heterozygous missense mutation in exon 2 (c.296G>A; Gly99Asp). The patient’s elder brother who had MLD is believed to have had the same mutation, which may be correlated with a rapidly deteriorating clinical course. This study identified a novel mutation in the ARSA gene, related to a late-infantile form of MLD with a lethal clinical course and suggested that molecular diagnosis of patients may be useful in early diagnosis and for deciding intervention measures for their family members. (Korean J Lab Med 2010;30:516-20)
참고문헌 (16)
- Lugowska A, "Homozygote for mutation c.1204+1G>A of the ARSA gene presents with a late-infantile form of metachromatic leukodystrophy and a rare MRI white matter lesion type", J Appl Genet, 46, pp.337~339 (2005)
- Coulter-Mackie MB, "Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene", J Med Genet, 34, pp.493~498 (1997)
- Zlotogora J, "A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy", J Med Genet, 31, pp.672~674 (1994)
- Gieselmann V, "Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options", Acta Paediatr Suppl, 97, pp.15~21 (2008)
- Barth ML, "The arylsulphatase A gene and molecular genetics of metachromatic leucodystrophy", J Med Genet, 31, pp.663~666 (1994)
- Roh MR, "Two cases of late infantile metachromatic leukodystrophy", J Korean Pediatr Soc, 27, pp.1033~1039 (1984)
- Lee HJ, "Late infantile metachromatic leukodystrophy-arylsulfatase A assay in 24h urine", J Korean Pediatr Soc, 32, pp.978~983 (1989)
- Kim YJ, "Clinical and neurologic features of metachromatic leukodystrophy", J Korean Child Neurol Soc, 3, pp.31~42 (1995)
- Kreysing J, "Structure of the arylsulfatase A gene", Eur J Biochem, 191, pp.627~631 (1990)
- Rogan PK, "Information analysis of human splice site mutations", Hum Mutat, 12, pp.153~171 (1998)
- Kondo R, "Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy", Am J Hum Genet, 48, pp.971~978 (1991)
- Polten A, "Molecular basis of different forms of metachromatic leukodystrophy", N Engl J Med, 324, pp.18~22 (1991)
- Conzelmann E, "Partial enzyme deficiencies: residual activities and the development of neurological disorders", Dev Neurosci, 6, pp.58~71 (1983)
- Peters C, "Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines", Bone Marrow Transplant, 31, pp.229~239 (2003)
- Peters C, "Hematopoietic cell transplantation for storage diseases in Thomas hematopoietic cell transplantation" (2003), Blackwell Scientific