Additional Copies of the Proteolipid Protein Gene Causing Pelizaeus-Merzbacher Disease Arise by Separate Integration into the X Chromosome

The proteolipid protein gene ( PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X ch...

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Bibliographic Details
Published in:American journal of human genetics 2000-07, Vol.67 (1), p.14-22
Main Authors: Hodes, M.E., Woodward, Karen, Spinner, Nancy B., Emanuel, Beverly S., Enrico-Simon, Agnes, Kamholz, John, Stambolian, Dwight, Zackai, Elaine H., Pratt, Victoria M., Thomas, I.T., Crandall, Kerry, Dlouhy, Stephen R., Malcolm, Sue
Format: Article
Language:English
Subjects:
Biological and medical sciences
Child
Child, Preschool
Chromosome Inversion
Chromosomes, Artificial, Yeast - genetics
Cytogenetic Analysis
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Exons - genetics
Female
Gene Dosage
Gene Duplication
Genes, Duplicate - genetics
Heterozygote
Humans
In Situ Hybridization, Fluorescence
Infant
Male
Medical sciences
Mutagenesis, Insertional - genetics
Myelin Proteolipid Protein - genetics
Neurology
Pedigree
Pelizaeus-Merzbacher Disease - genetics
Polymorphism, Single-Stranded Conformational
Recombination, Genetic - genetics
X Chromosome - genetics
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Summary:The proteolipid protein gene ( PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.
ISSN:0002-9297
1537-6605
DOI:10.1086/302965