| 1. |
- Andersson, Kristofer, et al.
(författare)
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Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - A retrospective cohort study
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p. Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p. Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.
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| 2. |
- Chen, Yin Huai, et al.
(författare)
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Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
- 2020
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:3
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Tidskriftsartikel (refereegranskat)abstract
- The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- Handa, Atsuhiko, et al.
(författare)
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Skeletal Dysplasia Families: A Stepwise Approach to Diagnosis
- 2023
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Ingår i: Radiographics. - : RADIOLOGICAL SOC NORTH AMERICA (RSNA). - 0271-5333 .- 1527-1323. ; 43:5
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These disorders are rare individually, but collectively they are common (approximate incidence of one in 5000 births). Radiologists occasionally encounter skeletal dysplasias in daily practice. In the 1980s, Professor Juergen Spranger proposed a concept suitable for the diagnosis of skeletal dysplasias termed bone dysplasia families. He stated that (a) different bone dysplasias that share a similar skeletal pattern can be grouped into a “family,” (b) the final diagnosis is feasible through the provisional recognition of a pattern followed by a more careful analysis, and (c) families of bone dysplasias may be the result of similar pathogenetic mechanisms. The prototypes of bone dysplasia families include dysostosis multiplex family, achondroplasia family, spondyloepiphyseal dysplasia congenita family, and Larsen syndrome–otopalatodigital syndrome family. Since Spranger’s proposal, the concept of bone dysplasia families, along with advancing genetic techniques, has been validated and further expanded. Today, this molecularly proven concept enables a simple stepwise approach to be applied to the radiologic diagnosis of skeletal dysplasias. The first step is the categorization of a given case into a family based on pattern recognition, and the second step is more meticulous observation, such as identification of different severities of the same pattern or subtle but distinctive findings. Since major skeletal dysplasias are limited in number, radiologists can be familiar with the representative patterns of these disorders. The authors describe a stepwise radiologic approach to diagnosing major skeletal dysplasia families and review the clinical and genetic features of these disorders.
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| 8. |
- Hansson, Caisa M., et al.
(författare)
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Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus
- 2007
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8, s. 16-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. Results: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/ terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (∼550 kb and ∼250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. Conclusion: We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development.
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| 9. |
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| 10. |
- Kuchinskaya, Ekaterina, et al.
(författare)
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Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis
- 2016
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Ingår i: Orphanet Journal of Rare Diseases. - : BIOMED CENTRAL LTD. - 1750-1172. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Ischiospinal dysostosis (ISD) is a polytopic dysostosis characterized by ischial hypoplasia, multiple segmental anomalies of the cervicothoracic spine, hypoplasia of the lumbrosacral spine and occasionally associated with nephroblastomatosis. ISD is similar to, but milder than the lethal/semilethal condition termed diaphanospondylodysostosis (DSD), which is associated with homozygous or compound heterozygous mutations of bone morphogenetic protein-binding endothelial regulator protein (BMPER) gene. Here we report for the first time biallelic BMPER mutations in two patients with ISD, neither of whom had renal abnormalities. Our data supports and further extends the phenotypic variability of BMPER-related skeletal disorders.
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