A point mutation in the FMR-1 gene associated with fragile X mental retardation

Abstract

The vast majority of patients with fragile X syndrome show a folate-sensitive fragile site at Xq27.3 (FRAXA) at the cytogenetic level, and both amplification of the (CGG)n repeat and hypermethylation of the CpG island in the 5' fragile X gene (FMR-1) at the molecular level. We have studied the FMR-1 gene of a patient with the fragile X phenotype but without cytogenetic expression of FRAXA, a (CGG)n repeat of normal length and an unmethylated CpG island. We find a single point mutation in FMR-1 resulting in an lle367Asn substitution. This de novo mutation is absent in the patient's family and in 130 control X chromosomes, suggesting that the mutation causes the clinical abnormalities. Our results suggest that mutations in FMR-1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.

Fragile X syndrome due to a missense mutation

“…12 One might ask why so few missense mutations have been identified in FMR1? This gene does not appear any less mutable than other typical X-linked genes.…”

“…However, a number of conventional mutations have also been demonstrated to lead to FXS. 11,12 Many FMR1 deletions have been reported, with most uncovered through absent or unexpected bands on a Southern blot used to diagnose the full mutation, or by microarray analysis. Nonsense and splice site mutations have also been reported in a limited number of patients.…”

“…Indeed, in over two decades since the discovery of FMR1 only a single missense mutation, isoleucine 304 to asparagine (p.(Ile304Asn)), has been reported. 12 Here we report a second missense mutation in FMR1, glycine 266 to glutamic acid (p.(Gly266Glu)), leading to FXS. This highlights the clinical utility of FMR1 sequencing, particularly at a time when gene sequencing is now more affordable and targeted therapeutics for FXS are being developed.…”

Chromosomal fragility and human genetic disorders

“…So far the mutations reported at the locus range from deletions of small but critical regions to deletions resulting in removal of the entire gene sequence (16,17,18), small insertions and deletions that lead to loss of function of FMR-1 (19). Point mutation leading to conversion of isoleucine to aspartic acid that results in Iossof function of FMR-1 lead to fragile -X syndrome (20). Molecular Study of FRAXE has shown that the fragility is due to an amplification of a GCC repeat adjacent to a CpG island.…”

Molecular genetic screening in cytogenetically normal mentally retarded males with manifestations of fragile X syndrome

“…While heterogeneous single base pair substitutions, small deletions, or insertions in the FMR-1 gene could produce a deficiency in the FMR-1 protein (FMRP) [Wöhrle et al, 1992;De Boulle et al, 1993;de Vries et al, 1993;Ashley et al, 1993], aberrations in other X-linked mental retardation genes, not identified to date, could also play a role in the causation of mental retardation in cytogenetically normal males.…”