Achondroplasia, the most common cause of chondrodysplasia in man (1 in 15,000 live births), is a condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. More than 90% of cases are sporadic and there is an increased paternal age at the time of conception of affected individuals, suggesting that de novo mutations are of paternal origin. Affected individuals are fertile and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, accounting for rare familial forms of the disease (10%). In contrast, homozygous achondroplasia is usually lethal in the neonatal period and affects 25% of the offspring of matings between heterozygous achondroplasia parents. The gene responsible for achondroplasia has been mapped to chromosome 4p16.3 (refs 7, 8); the genetic interval encompassing the disease gene contains a member of the fibroblast-growth-factor receptor (FGFR3) family which is expressed in articular chondrocytes. Here we report the finding of recurrent missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic cases and 6 unrelated familial forms of achondroplasia. We show that the mutant genotype segregates with the disease in these families. Thus it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
The spliceosome, a ribonucleoprotein complex that includes proteins and small nuclear RNAs (snRNAs), catalyzes RNA splicing through intron excision and exon ligation to produce mature messenger RNAs, which, in turn serve as templates for protein translation. We identified four point mutations in the U4atac snRNA component of the minor spliceosome in patients with brain and bone malformations and unexplained postnatal death [microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) or Taybi-Linder syndrome (TALS); Mendelian Inheritance in Man ID no. 210710]. Expression of a subgroup of genes, possibly linked to the disease phenotype, and minor intron splicing were affected in cell lines derived from TALS patients. Our findings demonstrate a crucial role of the minor spliceosome component U4atac snRNA in early human development and postnatal survival.
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