To characterize the genomic architecture of this region, we constructed PAC and BAC contigs and produced a finished sequenceĪcross this 1.4-Mb interval. 1996), raising the question as to whether such rare recombination events are mediated by other repeat units in this region. Furthermore, there are rare case reports of smaller duplications ( Ionasescu et al. Than PMP22 in this 1.4-Mb region somehow contribute to the variability of phenotypic manifestations or a combination of phenotypes (e.g.,ĬMT + connective tissue disorder). A formal possibility exists that minor dosage effect of genes other
Having the same 1.4-Mb duplication are quite variable. In addition, the clinical phenotypes of patients A question remains as to why only PMP22 is dosage sensitive, whereas other genes in the region are apparently not. Region on the basis of its genomic size ( Murakami et al. 1992).Īlthough duplication and deletion of PMP22 is the event responsible for CMT1A and HNPP, respectively, as many as 30 to 50 other genes may be contained in this 1.4-Mb Several lines of evidence indicate that gain of one copy of PMP22 is responsible for CMT1A, whereas loss of one copy of PMP22results in HNPP through a PMP22 gene dosage effect as the mechanism for these disorders ( Lupski et al. Subsequently, a gene encoding PMP22, a major component of the peripheral nervous system myelin, was mapped in the middle The CMT1A duplication and HNPP deletion represent products of unequal crossing over and a reciprocal recombination betweenįlanking 24-kb homologous sequences termed CMT1A–REPs ( Lupski 1998a). A submicroscopic deletion of the same region results in hereditary neuropathy with liability to pressure palsy (HNPP),Ī distinct form of inherited peripheral neuropathy with episodic and milder manifestations ( Chance et al. Molecular genetic approaches have identified a submicroscopic duplication of the 1.4-Mb genomic region in chromosome bandġ7p12 in the majority of the CMT1A cases ( Lupski et al. Neuropathy (for review, see Lupski and Garcia 2001). CMT1A is the most common inherited peripheral neuropathy and accounts for 70% of CMT type 1 inherited demyelinating Resulting from such genomic rearrangement may be categorized as genomic disorders in contrast to classic Mendelian diseasesĬaused by point mutations in the causative genes (for review, see Lupski 1998b Shaffer and Lupski 2000).Ĭharcot-Marie-Tooth disease type 1A (CMT1A) is one of the first and best-characterized examples of a submicroscopic genomicĭisorder. TheseĪre not visible by conventional karyotype assays and are thus likely to involve rearranged fragments smaller than 1–2 Mb.ĭisorders with these types of rearrangements may be caused by dosage effects of a single or multiple genes. Submicroscopic duplications/deletions represent genomic rearrangements that can be responsible for inherited diseases. The genomic region adjacent to proximal CMT1A–REP indicated an evolutionary mechanism for the formation of proximal CMT1A–REPĪnd the creation of novel genes by DNA rearrangement during primate speciation. Most of these predicted genes are expressed only in embryonic stages. New genes ( TEKT3, HS3ST3B1, NPD008/CGI-148, CDRT1, and CDRT15) and 13 predicted genes were identified. In addition to three previously described genes, five Recombination frequency in males may enable a chromosomal misalignment at proximal and distal CMT1A–REPs and promote unequalĬrossing over, which occurs 10 times more frequently in male meiosis. The sexes with a lower recombination frequency in males (0.67 cM/Mb) versus females (5.5 cM/Mb). Comparison between physical and genetic maps revealed a striking difference in recombination rates between A low copy number repeat (LCR) was identified, with one copy inside and two copies outside In this region, we constructed PAC and BAC contigs and determined the complete nucleotide sequence. To delineate genomic structural features, investigate higher-order genomic architecture, and identify genes Genomic structure of the 1.4-Mb region, including other genes contained within the rearranged genomic segment, remains essentially Genomic disorders wherein unique genome architectural features result in susceptibility to DNA rearrangements that cause disease.Ī gene within the 1.4-Mb region, PMP22, is responsible for these disorders through a gene-dosage effect in the heterozygous duplication or deletion.
Type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP).
Represent frequent genomic rearrangements resulting in two common inherited peripheral neuropathies, Charcot-Marie-Tooth disease Duplication and deletion of the 1.4-Mb region in 17p12 that is delimited by two 24-kb low copy number repeats (CMT1A–REPs)