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- 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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| 2. |
- Kedra, Darek
(författare)
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Characterization of candidate disease genes from human chromosomes 11g13 and 22q
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Two regions of the human genome, 11q13 and 22q, have been shown to harbor numerous disease-related genes, among them tumor suppressor genes (TSGs). The aim of this project was to construct transcription maps within these chromosomal segments, and thus provide a basis for further analysis of some of the genes for their involvement in disease-related processes. The main strategy used in identification of candidate genes was large-scale genomic sequencing combined with "in silico" cloning. In total 27 genes were cloned, including human paralogs and orthologs in other organisms. The following diseases have been assigned to 11q13: Bardet-Biedl syndrome; spino-cerebellar ataxia type 5; familial paraganglioma type 2; insulin dependent diabetes mellitus; the translocation t(11;17) in B-cell non-Hodgkin's lymphoma; and multiple endocrine neo-plasia type 1 (MEN 1). Our aim was to identify genes in the vicinity of PYGM and FAU loci using a comparative genomic sequencing approach. We sequenced a PAC around the PYGM locus from human 11q13 and a cosmid from Fugu rubripes containing the Pygm gene. The region surrounding Pygm locus in F. Rubripes was not syntenic with the region neighboring the human PYGM gene. We established a transcriptional map around the human PYGM gene which includes: i) two genes previously localized to 11q13, PYGM and a zinc-finger protein (ZFM1) gene; ii) germinal center kinase (GCK) gene; iii) a novel human CDC25-like (HCDC25L) gene; iv) a dystrophia myotonica protein kinase-like (DMPKL) gene; and v) a novel ubiquitously expressed gene of unknown function (germinal center kinase neighboring gene, GCKNG). The GCKNG gene was also cloned by other groups and confirmed to be the MEN1 tumor suppressor gene. Deletions on 22q have been described in multiple tumors, which implies that this chromosome harbors TSGs. Previous deletion mapping studies in meningiomas have defined four candidate regions on 22q. From one of these the neurofibromatosis type 2 gene (NF2) was cloned and shown to be inactivated in a subset of meningiomas. However, further studies indicate that additional 22q-located gene(s) may be important in development of these and other tumors. We analyzed six genes from meningioma-deleted regions on 22q. These were: clathrin heavy chain 2 gene (CLH-22); beta-prime adaptin gene (BAM22); human homologue of C. elegans NIPSNAP gene 1 (NIPSNAP1); synaptogyrin 1 gene (SYNGR1a, SYNGR1b, SYNGR1c); human homolog of chicken TOM1 gene (TOM1); and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1a, SMARCB1b). For the majority of these human genes, human paralogs and mouse orthologs were also investigated. This resulted in the characterization of a novel family of genes called synaptogyrins (SYNGR1-4), as well as NIPSNAP2 and TOM1L genes in humans. The human SMARCB1 gene is a tumor suppressor gene located on 22q11.2 and it is inactivated in malignant rhabdoid tumors. We performed mutational analysis of the SMARCB1 gene as well as CLH22, BAM22, and TOM1 genes in meningiomas and schwannomas with negative results. The closest paralogs of three genes (CLH-22, BAM22, and SYNGR1) studied in this thesis are located on human chromosome 17. Furthermore, the available literature and searches of databases show that 13 pairs of paralogs are located on chromosome 17 and 22. We propose that this is a result of an ancient chromosomal duplication event.
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| 3. |
- Rydzanicz, Malgorzata, et al.
(författare)
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Variable degree of mosaicism for tetrasomy 18p in phenotypically discordant monozygotic twins-Diagnostic implications
- 2021
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Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley-Blackwell. - 2324-9269. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post-zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs.Methods: Dysmorphic features and delayed neuro-motor development were observed in the proband, whereas her twin sister was phenotypically normal. Four tissues (blood, skin, hair follicles, and buccal mucosa) from both twins were studied using four complementary methods, including whole-exome sequencing, karyotyping, array CGH, and SNP array.Results: In the proband, tetrasomy 18p affecting all studied tissues except for blood was identified. Karyotyping of fibroblasts revealed isochromosome 18p [i(18p)] in all metaphases. The corresponding analysis of the phenotypically normal sister surprisingly revealed low-level mosaicism (5.4%) for i(18p) in fibroblasts.Conclusion: We emphasize that when mosaicism is suspected, multiple tissues should be studied and we highlight the usefulness of non-invasive sampling of hair follicles and buccal mucosa as a convenient source of non-mesoderm-derived DNA, which complements the analysis of mesoderm using blood. Moreover, low-level mosaic tetrasomy 18p is well tolerated and such low-level mosaicism, readily detected by karyotyping, can be missed by other methods. Finally, mosaicism for low-level tetrasomy 18p might be more common in the general population than it is currently recognized, due to detection limitations.
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