Human Molecular Genetics, Vol 5, 581-590, Copyright © 1996 by Oxford University Press
JC van Deutekom, RJ Lemmers, PK Grewal, M van Geel, S Romberg, HG Dauwerse, TJ Wright, GW Padberg, MH Hofker, JE Hewitt and RR Frants
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant,
neuromuscular disorder characterized by progressive weakness of muscles in
the face, shoulder and upper arm. Deletion of integral copies of a 3.3 kb
repeated unit from the subtelomeric region on chromosome 4q35 has been
shown to be associated with FSHD. These repeated units which are apparently
not transcribed, map very close to the 4q telomere and belong to a 3.3 kb
repeat family dispersed over heterochromatic regions of the genome. Hence,
position effect variegation (PEV), inducing allele-specific transcriptional
repression of a gene located more centromeric, has been postulated as the
underlying genetic mechanism of FSHD. This hypothesis has directed the
search for the FSHD gene to the region centromeric to the repeated units. A
CpG island was identified and found to be associated with the 5'
untranslated region of a novel human gene, FRG1 (FSHD Region Gene 1). This
evolutionary conserved gene is located about 100 kb proximal to the
repeated units and belongs to a multigene family with FRG1 related
sequences on multiple chromosomes. The mature chromosome 4 FRG1 transcript
is 1042 bp in length and contains nine exons which encode a putative
protein of 258 amino acid residues. Transcription of FRG1 was detected in
several human tissues including placenta, lymphocytes, brain and muscle. To
investigate a possible PEV mechanism, allele-specific FRG1 steady-state
transcript levels were determined using RNA-based single-strand
conformation polymorphism (SSCP) analysis. A polymorphic fragment contained
within the first exon of FRG1 was amplified from reverse transcribed RNA
from lymphocytes and muscle biopsies of patients and controls. No evidence
for PEV mediated repression of allelic transcription was obtained in these
tissues. However, detection of PEV in FSHD patients may require analysis of
more specific cell types at particular developmental stages.
ARTICLES
Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35
MGC-Department of Human Genetics, Leiden University, The Netherlands.
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