PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus-Merzbacher disease in a girl.
PLP1 (proteolipid protein1 gene) mutations cause Pelizaeus-Merzbacher disease (PMD), characterized by hypomyelination of the central nervous system, and affecting almost exclusively males. We report on a girl with classical PMD who carries an apparently balanced translocation t(X;22)(q22;q13). By applying array-based comparative genomic hybridization (a-CGH), we detected duplications at 22q13 and Xq22, encompassing 487-546 kb and 543-611 kb, respectively. The additional copies were mapped by fluorescent in situ hybridization to the breakpoint regions, on the derivative X chromosome (22q13 duplicated segment) and on the derivative 22 chromosome (Xq22 duplicated segment). One of the 14 duplicated X-chromosome genes was PLP1.The normal X chromosome was the inactive one in the majority of peripheral blood leukocytes, a pattern of inactivation that makes cells functionally balanced for the translocated segments. However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X-inactivation pattern, thus causing PMD. This t(X;22) is the first constitutional human apparently balanced translocation with duplications from both involved chromosomes detected at the breakpoint regions.
Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
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Fonseca
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Bonaldi
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Freitas
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Vianna-Morgante
D002892:Chromosomes, Human, Pair 22; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000175:diagnosis / Q000235:genetics*; D014178:Translocation, Genetic
D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human