A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia

Abstract

Hypochondroplasia and achondroplasia are skeletal dysplasias, characterized by autosomal dominant inheritance and disproportionate short stature, which occurs mainly due to growth failure of the extremities. Both dysplasias have been mapped to fibroblast growth factor receptor 3 (FGFR3) gene. For hypochondroplasia, two point mutations, both responsible for the Asn540Lys substitution in the region coding the tyrosine kinase domain have been reported. Here we report an A to G transition at position 1651, predicting an Ile538Val substitution in the FGFR3, in hypochondroplasia. The substitution is found in a swedish family with three affected members. The criteria for hypochondroplasia were disproportionate short stature and radiological evidence of shortened long bones and decrease or absence of normal increase in interpedicular distances of the lumbar column. The mutation was detected by direct sequencing and restriction enzyme Tai I digestion. The base change was not found in the FGFR3 genes of unaffected members of the family nor in seventy-five unrelated unaffected individuals, suggesting that it was not a polymorphism. The Ile538Val substitution is a conservative amino acid change (a hydrophobic amino acid incorporated for another hydrophobic amino acid). Nevertheless, it is located in the stretch of nine amino acids, which is highly conserved among all the human fibroblast growth factor receptors. Considering the location of this substitution and the segregation with the phenotype in this family, we propose that it is a causative mutation of hypochondroplasia. It is difficult to establish whether the Ile538Val substitution is rare in hypochondroplasia patients or whether the individuals, who have a moderate degree of short stature, rarely seek medical help for the short stature and consequently are rarely diagnosed as affected by hypochondroplasia.

Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia

“…The known mutation p.Ile538Val found in our patient is located in the highly conserved tyrosine kinase domain of FGFR3 (Supplementary Figure S1). This mutation has been previously reported in a Swedish family with typical HCH (Grigelioniene et al, ). The p.Ile538Val mutation in the FGFR3 gene was expected to cause weak FGFR3 activation and aberrant RAS/ERK pathway (Krejci, ; Ornitz & Legeai‐Mallet, ).…”

The new bone biology: Pathologic, molecular, and clinical correlates

“…Genetic heterogeneity has been found in some families by excluding linkage to 4p16.3 [Stoilov et al, 1995; Rousseau et al, 1996a; Grigelioniene et al, 1998]. Other mutations have been found in isolated families, including Ile538Val [Grigelioniene et al, 1998], Asn540Thr [Deutz‐Terlouw et al, 1998], Asn328Ile [Winterpacht et al, 2000], and Asn540Ser [Mortier et al, 2000] (Table XXIII).…”

Hypochondroplasia and stature within normal limits: Another family with an Asn540Ser mutation in the fibroblast growth factor receptor 3 gene

“…Nine different FGFR3 missense mutations resulting in seven different amino acid substitutions are described: one in exon 9 (N328I), four in exon 13 (N540K, N540T, N540S, and I538V) and two in exon 15 (K650N and K650Q). The most frequent, N540K, accounts for more than 50% of all FGFR3 mutations in hypochondroplasia [Bellus et al, 1995; Prinos et al, 1995; Bonaventure et al, 1996; Deutz‐Terlouw et al, 1998; Grigelioniene et al, 1998; Matsui et al, 1998; Bellus et al, 2000; Mortier et al, 2000; Winterpacht et al, 2000]. Patients with N540K mutation tend to have more severe short stature and more disproportion than patients with other mutations.…”

“…Patients with N540K mutation tend to have more severe short stature and more disproportion than patients with other mutations. However, macrocephaly appears to be more severe in patients with the K650N and K650Q mutations than in patients with the other mutations (Table I) [Grigelioniene et al, 1998; Bellus et al, 2000; Winterpacht et al, 2000].…”