Inheritance of Charcot–Marie–Tooth disease 1A with rare nonrecurrent genomic rearrangement

• Published in: Neurogenetics Vol. 12; no. 1; pp. 51 - 58
• Main Authors: Choi, Byung-Ok, Kim, Nam Keun, Park, Sun Wha, Hyun, Young Se, Jeon, Hyeon Jeong, Hwang, Jung Hee, Chung, Ki Wha
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2011; Springer; Springer Nature B.V
• Subjects: Alu Elements; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Charcot-Marie-Tooth Disease - genetics; Chromosomes, Human, Pair 17 - genetics; Comparative Genomic Hybridization; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA - genetics; DNA Copy Number Variations; Female; Fundamental and applied biological sciences. Psychology; Gene Rearrangement; Genetic disorders; Genetic recombination; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Human Genetics; Humans; Male; Medical sciences; Models, Genetic; Molecular and cellular biology; Molecular Medicine; Neurology; Neuromuscular diseases; Neurosciences; Oligonucleotide Array Sequence Analysis; Original Article; Pedigree; Phenotype; Polymerase Chain Reaction; Republic of Korea; Vertebrates: nervous system and sense organs; Republic of Korea; sequence; Nonrecurrent rearrangement; Charcot–Marie–Tooth disease 1A (CMT1A); MMBIR; Copy number variation; FoSTeS; Neuromuscular diseases; Nervous system diseases; Copy number; Inheritance; Variations; Charcot―Marie―Tooth disease 1A (CMT1A); Transposable element; Genetic disease; Neurology; Alu sequence; Charcot-Marie-Tooth disease; Central nervous system disease; PMP22; Genetics; Degenerative disease; Spinal cord disease
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-010-0272-3

Rare copy number variations by the nonrecurrent rearrangements involving PMP22 have been recently suggested to be associated with CMT1A peripheral neuropathy. As a mechanism of the nonrecurrent rearrangement, replication-based fork stalling template switching (FoSTeS) by microhomology-mediated break-induced replication (MMBIR) has been proposed. We found three Korean CMT1A families with putative nonrecurrent duplication. The duplications were identified by microsatellite typing and applying a CGH microarray. The breakpoint sequences in two families suggested an Alu–Alu -mediated rearrangement with the FoSTeS by the MMBIR, and a two-step rearrangement of the replication-based FoSTeS/MMBIR and meiosis-based recombination. The two-step mechanism has still not been reported. Segregation analysis of 17p12 microsatellite markers and breakpoint junction analysis suggested that the nonrecurrent rearrangements are stably inherited without alteration of junction sequence; however, they may allow some alteration of the genomic contents in duplication across generations by recombination event. It might be the first study on the pedigree analysis of the large CMT1A families with nonrecurrent rearrangements. It seems that the exact mechanism of the nonrecurrent rearrangements in the CMT1A may have a far more complex process than has been expected.