PMID- 10319885
OWN - NLM
STAT- MEDLINE
DCOM- 19990525
LR  - 20071114
IS  - 0364-5134 (Print)
IS  - 0364-5134 (Linking)
VI  - 45
IP  - 5
DP  - 1999 May
TI  - Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: 
      molecular mechanism and phenotypic manifestations.
PG  - 624-32
AB  - Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder characterized by 
      dysmyelination of the central nervous system (CNS) caused by mutations involving 
      the proteolipid protein gene (PLP). In addition to point and frameshift mutations 
      in the coding region, duplications involving the entire PLP have been recognized 
      recently as a major genetic abnormality causing PMD. We devised an interphase 
      fluorescence in situ hybridization (FISH) assay to establish an efficient 
      screening test for PLP duplication. Thirteen patients from 11 Japanese PMD 
      families were determined to have PLP duplications. This molecular diagnostic FISH 
      test also readily detected female carriers. Molecular analysis revealed that the 
      size of the duplication and location of the breakpoints showed striking 
      variation. Fiber FISH demonstrated that the duplication is tandem in nature. 
      Haplotype analysis indicated an intrachromosomal origin for the duplication. 
      These results suggest that an unequal sister chromatid exchange in male meiosis 
      is likely to be the major mechanism leading to the formation of the duplication. 
      Patients with the duplication commonly present with a mild PMD phenotype. Two 
      patients with an exceptionally severe clinical phenotype carried large 
      duplications, suggesting that either the larger duplicated segment incorporates 
      additional dosage-sensitive genes or that the location of the duplication 
      junction may affect the phenotype.
FAU - Inoue, K
AU  - Inoue K
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      TX 77030, USA.
FAU - Osaka, H
AU  - Osaka H
FAU - Imaizumi, K
AU  - Imaizumi K
FAU - Nezu, A
AU  - Nezu A
FAU - Takanashi, J
AU  - Takanashi J
FAU - Arii, J
AU  - Arii J
FAU - Murayama, K
AU  - Murayama K
FAU - Ono, J
AU  - Ono J
FAU - Kikawa, Y
AU  - Kikawa Y
FAU - Mito, T
AU  - Mito T
FAU - Shaffer, L G
AU  - Shaffer LG
FAU - Lupski, J R
AU  - Lupski JR
LA  - eng
GR  - R01NS27042/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (Myelin Proteolipid Protein)
SB  - IM
MH  - Adolescent
MH  - Alleles
MH  - Child
MH  - Child, Preschool
MH  - Chromosome Mapping
MH  - Diffuse Cerebral Sclerosis of Schilder/*genetics
MH  - Female
MH  - *Gene Duplication
MH  - Haplotypes
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Myelin Proteolipid Protein/*genetics
MH  - Phenotype
EDAT- 1999/05/13 00:00
MHDA- 1999/05/13 00:01
CRDT- 1999/05/13 00:00
PHST- 1999/05/13 00:00 [pubmed]
PHST- 1999/05/13 00:01 [medline]
PHST- 1999/05/13 00:00 [entrez]
PST - ppublish
SO  - Ann Neurol. 1999 May;45(5):624-32.