PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus-Merzbacher disease in a girl

Author(s)

Fonseca, A. C. S. ; Bonaldi, A. ; Costa, S. S. ; Freitas, M. R. ^[1] ; Kok, F. ^[1] ; Vianna-Morgante, A. M. ^[2]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Dept Neurol, BR-05508090 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Fac Med, BR-05508090 Sao Paulo - Brazil

• Document type: Journal article
• Source: Clinical Genetics; v. 83, n. 2, p. 169-174, FEB 2013.
• Web of Science Citations: 7

Abstract

Fonseca ACS, Bonaldi A, Costa SS, Freitas MR, Kok F, Vianna-Morgante AM. PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes PelizaeusMerzbacher disease in a girl. PLP1 (proteolipid protein1 gene) mutations cause PelizaeusMerzbacher 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 487546 kb and 543611 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. (AU)

• FAPESP's process: 09/03480-8 - Characterization of apparently balanced chromosomal rearrangements associated with clinical phenotypes: breakpoint mapping and screening for submicroscopic deletions and duplications
• Grantee: Ana Carolina dos Santos Fonseca
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 09/00898-1 - Submicroscopic genomic imbalances associated with specific congenital abnormalities and mental deficiency phenotypes
• Grantee: Carla Rosenberg
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 98/14254-2 - The Human Genome Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC