PMID- 10545611
OWN - NLM
STAT- MEDLINE
DCOM- 19991214
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 12
DP  - 1999 Nov
TI  - Novel mutations and genotype-phenotype relationships in 107 families with
      Fukuyama-type congenital muscular dystrophy (FCMD).
PG  - 2303-9
AB  - Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common
      autosomal recessive disorders in the Japanese population, is characterized by
      congenital muscular dystrophy in combination with cortical dysgenesis
      (micropolygyria). Recently, we identified, on chromosome 9q31, the gene
      responsible for FCMD, which encodes a novel 461 amino acid protein which we have 
      termed fukutin. Most FCMD-bearing chromosomes examined to date (87%) have been
      derived from a single ancestral founder, whose mutation consisted of a 3 kb
      retrotransposal insertion in the 3' non-coding region of the fukutin gene. FCMD
      is the first human disease known to be caused primarily by an ancient
      retrotransposal integration. We under-took a systematic analysis of the FCMD gene
      in 107 unrelated patients, and identified four novel non-founder mutations in
      five of them: one missense, one nonsense, one L1 insertion and a 1 bp insertion. 
      The frequency of severe phenotypes, including Walker-Walberg syndrome-like
      manifestations such as hydrocephalus and microphthalmia, was significantly higher
      among probands who were compound heterozygotes carrying a point mutation on one
      allele and the founder mutation on the other, than it was among probands who were
      homozygous for the 3 kb retrotransposon. Remarkably, we detected no FCMD patients
      with non-founder (point) mutations on both alleles of the gene, and suggest that 
      such cases might be embryonic-lethal. This could explain why few FCMD cases are
      reported in non-Japanese populations. Our results provided strong evidence that
      loss of function of fukutin is the major cause of FCMD, and appeared to shed some
      light on the mechanism responsible for the broad clinical spectrum seen in this
      disease.
FAU - Kondo-Iida, E
AU  - Kondo-Iida E
AD  - Laboratory of Genome Medicine, Human Genome Center, Institute of Medical Science,
      University of Tokyo, Japan.
FAU - Kobayashi, K
AU  - Kobayashi K
FAU - Watanabe, M
AU  - Watanabe M
FAU - Sasaki, J
AU  - Sasaki J
FAU - Kumagai, T
AU  - Kumagai T
FAU - Koide, H
AU  - Koide H
FAU - Saito, K
AU  - Saito K
FAU - Osawa, M
AU  - Osawa M
FAU - Nakamura, Y
AU  - Nakamura Y
FAU - Toda, T
AU  - Toda T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DNA Primers)
RN  - 0 (FKTN protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (Proteins)
SB  - IM
MH  - Base Sequence
MH  - DNA Primers
MH  - Genotype
MH  - Humans
MH  - Membrane Proteins
MH  - Muscular Dystrophies/congenital/*genetics
MH  - *Mutation
MH  - Phenotype
MH  - Proteins/*genetics
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - ddc260 [pii]
AID - 10.1093/hmg/8.12.2303 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Nov;8(12):2303-9. doi: 10.1093/hmg/8.12.2303.