The CMT1A-REP Binary Repeat  from Disease Causing Genomic Re-arrangements to a Role in Gene Evolution

M.   L.   Kennerson; N.   T.   Nassif; G.   A.   Nicholson

Abstract

The CMT1A-REP binary repeat consists of two homologous regions of DNA, a proximal CMT1A-REP element and a distal CMT1A-REP element, that flank a 1.5 Mb DNA segment on chromosome 17p11.2-p12. Misalignment between sequences within the two elements of this binary repeat during homologous recombination causes two inherited peripheral neuropathies, Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). Despite contributing to the instability of this region of chromosome 17, CMT1A-REP is maintained as a binary repeat in chimpanzees and all human populations of different ethnic origin. Two genes mapping wholly, or partially, within the binary repeat have been recently identified. The distal CMT1A-REP element is known to lie within the COX10 gene and a duplicated pseudo exon of this gene is present in the proximal CMT1A-REP element. A second gene, C17ORF1A, localises partially within the proximal CMT1A-REP element. This gene includes the duplicated COX10 exon and part of the flanking intronic sequences within its coding region. The sequences derived from the COX10 gene form part of the open reading frame and 3 untranslated region of C17ORF1A by the utilisation of the opposite DNA strand to that used in the COX10 gene. The antisense nature of C17ORF1A raises the possibility of C17ORF1A acting as a down regulator of the COX10 gene. This review will highlight the unique features of this disease-causing repeat and its role in the formation of a previously undescribed gene that appears to be present only in humans and primates.

Keywords: The CMT1A-REP Binary Repeat, Genomic Re-arrangements, Gene Evolution, Charcot Marie Tooth type 1A CMTI, Homologous sequence, C17ORF1A, CMT1A REP

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