| 1. |
- Grigelioniene, Giedre, et al.
(författare)
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Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity
- 2001
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 109:5, s. 551-558
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Tidskriftsartikel (refereegranskat)abstract
- Dyschondrosteosis (DCO; also called Leri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.
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| 2. |
- Grigelioniene, Giedre, et al.
(författare)
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Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in hypochondroplasia
- 2000
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 89:9, s. 1072-1076
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Tidskriftsartikel (refereegranskat)abstract
- Hypochondroplasia is characterized by a disproportionate short stature with rhizomelic shortening of the limbs. Amino acid substitutions Asn540Lys, Asn540Thr and Ile538Val in the fibroblast growth factor receptor 3 (FGFR3) are considered to cause hypochondroplasia. In this study we examined the FGFR3 gene for the previously described hypochondroplasia mutations and the phenotype of 23 probands with clinically and radiologically diagnosed hypochondroplasia. For the phenotype comparison, the patients were divided into two groups: Group 1: hypochondroplasia with Asn540Lys substitution; Group 2: hypochondroplasia with no mutations identified so far. A three-generation family negative for the known hypochondroplasia mutations was examined with polymorphic markers flanking the FGFR1, FGFR2 and FGFR3 genes. Nine (39%) of 23 probands were found to be heterozygous for the Asn540Lys substitution. The individuals positive for the Asn540Lys substitution were significantly more disproportionate than the individuals without this mutation. In this respect, a genotype-phenotype correlation was found in our patients. However, some individuals belonging to the group without mutations identified so far showed similarly abnormal proportions. Genotyping/haplotyping in the three-generation family with hypochondroplasia showed that FGFR1, FGFR2 and FGFR3 genes were not linked to the hypochondroplasia phenotype in this family, thus further confirming the genetic heterogeneity of hypochondroplasia. CONCLUSION: Individuals with hypochondroplasia heterozygous for the Asn540Lys substitution are significantly more disproportionate than individuals without this mutation. Our study further confirms the clinical and genetic heterogeneity of hypochondroplasia.
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| 3. |
- Grigelioniene, Giedre
(författare)
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Clinical and genetic investigation of hypochondroplasia and dyschondrosteosis
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Linear body growth is a multifactorial trait influenced by many environmental and intrinsic factors. Among the intrinsic determinants of body height, genetic and endocrine factors are considered to be the most important. Children with short stature are usually referred to paediatric endocrinology clinics and a significant proportion of these suffer from skeletal dysplasias. Hypochondroplasia and dyschondrosteosis (Léri-Weill syndrome) are characterised by disproportionate short stature. The phenotype in hypochondroplasia is mainly characterised by rhizomelic (proximal) shortening of the limbs, whereas dyschondrosteosis confers mesomelic short stature (shortening of the middle segment). An aberration of the forearm, called Madelung deformity, is a frequent feature of dyschondrosteosis. In both hypochondroplasia and dyschondrosteosis, the phenotype varies from moderate to severe short stature and body disproportion and it is usually mild in early childhood, which causes diagnostic difficulties. In these cases, molecular genetic analysis is an important diagnostic tool. Point mutations in the FGFR3 (fibroblast growth factor receptor 3) gene, causing the Asn54OLys substitution, have been described in 40-70% of hypochondroplasia cases. Haploinsufficiency of the SHOX (short stature homeobox-containing) gene due to deletions or point mutations has been found in dyschondrosteosis and in some cases of idiopathic short stature. In this study, the frequency of the Asn540Lys mutation was determined in 30 Swedish probands with clinically and radiologically confirmed hypochondroplasia. Nine unrelated individuals were found to be heterozygous for the Asn54OLys mutation, whereas one proband in a familial case with hypochondroplasia was found to have a novel mutation IIe538Val. Overall, FGFR3 mutations were found in only 33% of hypochondroplasia probands. In a single three-generation hypochondroplasia family, we excluded involvement of FGFR3, which supports the genetic heterogeneity in hypochondroplasia. The hypochondroplasia individuals without the Asn540Lys mutation were less disproportionate, suggesting that these cases might have a phenotype resembling idiopathic short stature or mild dyschondrosteosis. Considering the above-mentioned findings and clinical overlap between hypochondroplasia and dyschondrosteosis, we analysed 18 probands with hypochondroplasia (negative for the known FGFR3 mutations) and 32 probands with dyschondrosteosis, for mutations in the SHOX gene. In dyschondrosteosis group, 16 unrelated families (50%) had SHOX gene deletions, whereas 9 probands (28%) carried point mutations/minute deletions in the SHOX gene. In total 78% of the probands with dyschondrosteosis had mutations in the SHOX gene and seven mutations were previously not described. All novel mutations segregated with the dyschondrosteosis phenotype in familial cases and were not found in 90 unrelated, unaffected individuals, suggesting that these mutations are pathogenic. No SHOX mutations were found in hypochondroplasia individuals lacking known FGFR3 gene mutations, which suggests that SHOX gene defects are not involved in the pathogenesis of hypochondroplasia. Considering a high percentage of SHOX gene mutations in dyschondrosteosis and difficulties in differential diagnosis between hypochondroplasia and dyschondrosteosis, especially in children, molecular analysis of SHOX gene could be an important diagnostic tool. Seven sporadic cases with isolated Madelung deformity were also examined and no SHOX gene mutations that could be considered pathogenic were identified. Thus, it is less likely that mutations in the SHOX gene are involved in the development of isolated Madelung deformity.
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| 4. |
- Grigelioniene, Giedre, et al.
(författare)
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Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia
- 2000
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 107:2, s. 145-149
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Tidskriftsartikel (refereegranskat)abstract
- Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.
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