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Case Reports
. 2000 Jul;67(1):14-22.
doi: 10.1086/302965. Epub 2000 May 25.

Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome

M E Hodes  1 , K Woodward, N B Spinner, B S Emanuel, A Enrico-Simon, J Kamholz, D Stambolian, E H Zackai, V M Pratt, I T Thomas, K Crandall, S R Dlouhy, S Malcolm
Affiliations
Case Reports

Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome

M E Hodes et al. Am J Hum Genet. 2000 Jul.

Abstract

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.

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Figures

Figure 1
Figure 1
Pedigrees of families 1 (A) and 2 (B)
Figure 2
Figure 2
Separation of fragments of genomic DNA from family 1, after digestion by AhaII. Fragments of genomic DNA obtained by PCR amplification of exon 4 were digested by AhaII. Electrophoresis of the digest was performed in a 12% polyacrylamide gel. Lane 1 denotes a 100-bp ladder; lane 2, a male control who was AhaII negative; lane 3, a male control who was AhaII positive; lane 4, patient III-1; lane 5, patient III-2; lane 6, patient IV-1; lane 7, patient IV-2; lane 8, patient IV-10; lane 9, patient III-12; lane 10, patient II-12; lane 11, a female control who was heterozygous; and lane 12, distilled water.
Figure 3
Figure 3
FISH analysis of the families. Metaphase chromosome spread (A) and interphase nucleus (B) from the propositus in figure 1A, as hybridized with a PLP cosmid probe (yellow) and an X chromosome centromeric probe (red). The signal on chromosome Xq22 shows the normal PLP gene, and the signal on Xp22.1 shows the PLP duplication. The two clearly resolvable yellow signals in the interphase nucleus show the PLP duplication on either side of the red centromeric signal. C, Metaphase chromosome spread from the propositus in family 2. Hybridization was with the YAC 122e11 probe. D, Single PLP signal from control metaphase spread.
See this image and copyright information in PMC

Comment in

  • Breaking away from home.
    Hudson LD. Hudson LD. Am J Hum Genet. 2000 Jul;67(1):1-3. doi: 10.1086/302982. Epub 2000 May 25. Am J Hum Genet. 2000. PMID: 10827110 Free PMC article. No abstract available.

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References

Electronic-Database Information

    1. GenBank Genetic Sequence Database, http://helix.nih.gov/science/genbank.html
    1. Human Genome Sequencing Center, Baylor College of Medicine, http://www.hgsc.bcm.tmc.edu/index.html (for three YACs [122e11, 226c9, and 526g7] containing the PLP gene)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for PMD [MIM 312080] and X-linked SPG2 [MIM 312920])
    1. Sanger Centre, The, http://www.sanger.ac.uk/HGP/ChrX/

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