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1.
Linkage of the gene that encodes the {alpha}1 chain of type V collagen (COL5A1) to type II Ehlers-Danlos syndrome (EDS II) 总被引:1,自引:0,他引:1
Loughlin John; Irven Catherine; Hardwick Lee J.; Butcher Sophie; Walsh Sinead; Wordsworth Paul; Sykes Bryan 《Human molecular genetics》1995,4(9):1649-1651
Ehlers-Danlos syndrome (EDS) is a group of heritable disordersof connective tissue with skin, ligaments and blood vesselsbeing the main sites affected. The commonest variant (EDS II)exhibits an autosomal dominant mode of inheritance and is characterizedby joint hypermobility, cigarette paper scars, lax skin andexcessive brusing. As yet no gene has been linked to EDS II,nor has linkage been established to a specific region of thegenome. However, several candidate genes encoding proteins ofthe extracellular matrix have been excluded. Using an intragenicsimple sequence repeat polymorphism, we report linkage of theCOL5A1 gene, which encodes the 相似文献
2.
A J Richards S Martin A C Nicholls J B Harrison F M Pope N P Burrows 《Journal of medical genetics》1998,35(10):846-848
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders. Recently mutations have been found in the genes for type V collagen in a small number of people with the most common forms of EDS, types I and II. Here we characterise a COL5A2 mutation in an EDS II family. Cultured dermal fibroblasts obtained from an affected subject synthesised abnormal type V collagen. Haplotype analysis excluded COL5A1 but was concordant with COL5A2 as the disease locus. The entire open reading frame of the COL5A2 cDNA was directly sequenced and a single base mutation detected. It substituted a glycine residue within the triple helical domain (G934R) of alpha2(V) collagen, typical of the dominant negative changes in other collagens, which cause various other inherited connective tissue disorders. All three affected family members possessed the single base change, which was absent in 50 normal chromosomes. 相似文献
3.
A T+6 to C+6 mutation in the donor splice site of COL3A1 IVS7 causes exon skipping and results in Ehlers-Danlos syndrome type IV. 总被引:1,自引:1,他引:1 下载免费PDF全文
Ehlers-Danlos syndrome type IV is usually caused by mutations in COL3A1, the gene coding for type III collagen. In a woman with a milder form of this disease, analysis of type III collagen synthesised by her cultured skin fibroblasts showed an apparently shorter form of the protein. Amplification of overlapping cDNAs, encoding the triple helical region of the molecule, showed a deletion near the 5' end of the gene. Sequencing showed that exon 7 was missing from the cDNA sequence. Analysis of genomic DNA showed that this was the result of a T+6 to C+6 mutation in the donor splice site of intron 7. The proband's parents and 35 normal controls were homozygous for T+6 at this position, indicating that the C+6 mutation was causative. 相似文献
4.
Bernhard Zabel Katja Hilbert Hartmut Stß Andrea Superti-Furga Jürgen Spranger Andreas Winterpacht 《American journal of medical genetics. Part A》1996,63(1):123-128
We report on a patient with a skeletal dysplasia characterized by short stature, spondylo-epiphyseal involvement, and brachydactyly E-like changes. This condition has been described as spondyloperipheral dysplasia and the few published cases suggest autosomal dominant inheritance with considerable clinical variability. We found our sporadic case to be due to a collagen type II defect resulting from a specific COL2A1 mutation. This mutation is the first to be located at the C-terminal outside the helical domain of COL2A1. A frameshift as consequence of a 5 bp duplication in exon 51 leads to a stop codon. The resulting truncated C-propeptide region seems to affect helix formation and produces changes of chondrocyte morphology, collagen type II fibril structure and cartilage matrix composition. Our case with its distinct phenotype adds another chondrodysplasia to the clinical spectrum of type II collagenopathies. © 1996 Wiley-Liss, Inc. 相似文献
5.
Ehlers-Danlos syndrome type IV: phenotypic consequences of a splicing mutation in one COL3A1 allele. 总被引:1,自引:0,他引:1 下载免费PDF全文
The features of a child with Ehlers-Danlos syndrome type IV (EDS IV) resulting from a mutation in one COL3A1 allele were studied. The child was heterozygous for a G- to A-transition at the splice donor site of intron 41. It resulted in the splicing out of the exon 41 encoded sequence from alpha 1(III) mRNA and the deletion of 36 amino acids from glycine775 to lysine810 of the triple helical domain of alpha 1(III) chains of type III collagen. The amount of type III collagen in the dermis was only about 11% of normal. The child had the acrogeric form of EDS IV. He had the characteristic facies with a pinched nose, thin lips, and prominent eyes. These facial features, his aesthenic build, thin skin, prominent subcutaneous veins, and aged hands produced a 'cachectic' appearance. These features were evident in early childhood and worsened up to 12 1/2 years when he was last reviewed. Spontaneous bruising, bleeding from the large bowel, constipation, and delayed gastric emptying were other features. In cross section, the dermal collagen fibrils were round and measured 93.3 +/- 11.5 nm in diameter which was not significantly different from control values of 102.5 +/- 13.4 nm. The serum type III procollagen amino-terminal propeptide level of 25.5 ng/ml was within the normal age matched values of 15.5 +/- 7.7 ng/ml despite the low production of type III collagen by cultured fibroblasts. The child probably had a spontaneous new mutation in one COL3A1 allele as only normal sequences were obtained from the corresponding amplified region of the parent's leucocyte DNA. 相似文献
6.
Peter H. Byers Madeleine Duvic Mary Atkinson Meinhard Robinow Lynne T. Smith Stephen M. Krane Marie T. Greally Mark Ludman Reuben Matalon Susan Pauker Deborah Quanbeck Ulrike Schwarze 《American journal of medical genetics. Part A》1997,72(1):94-105
Ehlers-Danlos syndrome (EDS) type VII results from defects in the conversion of type I procollagen to collagen as a consequence of mutations in the substrate that alter the protease cleavage site (EDS type VIIA and VIIB) or in the protease itself (EDS type VIIC). We identified seven additional families in which EDS type VII is either dominantly inherited (one family with EDS type VIIB) or due to new dominant mutations (one family with EDS type VIIA and five families with EDS type VIIB). In six families, the mutations alter the consensus splice junctions, and, in the seventh family, the exon is deleted entirely. The COL1A1 mutation produced the most severe phenotypic effects, whereas those in the COL1A2 gene, regardless of the location or effect, produced congenital hip dislocation and other joint instability that was sometimes very marked. Fractures are seen in some people with EDS type VII, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. These new findings expand the array of mutations known to cause EDS type VII and provide insight into genotype/phenotype relationships in these genes. Am. J. Med. Genet. 72:94–105, 1997. © 1997 Wiley-Liss, Inc. 相似文献
7.
Vuoristo MM Pappas JG Jansen V Ala-Kokko L 《American journal of medical genetics. Part A》2004,(2):160-164
Mutations in COL11A2 cause a spectrum of phenotypes affecting chondrogenic tissues. We analyzed this gene by conformation sensitive gel electrophoresis (CSGE) and sequencing in a family with non-ocular Stickler syndrome, and found a heterozygous C --> T mutation in exon 57 + 13 in affected members, resulting in Arg893Stop codon. Since heterozygous nonsense mutations in COL11A2 do not usually lead to any obvious phenotype, all exons and exon boundaries of COL11A2 in the sample of the propositus were sequenced. Because no disease-associated alterations were found, we performed RT-PCR analysis on the RNA. Analysis showed skipping of exon 57 in one allele, resulting in an inframe deletion of 54 bp or 18 amino acids, which would explain the phenotype observed in the family. Thus, the exon skipping resulted from a nonsense-associated altered splicing (NAS). This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html. 相似文献
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A mother and son with Ehlers-Danlos syndrome (EDS) type IV and unusual congenital anomalies are described. The congenital anomalies include, in the mother, amniotic band-like constrictions on one hand, a unilateral clubfoot, and macrocephaly owing to normal-pressure hydrocephaly and, in the son, an esophageal atresia and hydrocephaly. Protein analysis of collagen III in cultured fibroblasts of the mother showed no abnormalities. However, DNA analysis of the COL3A1 gene revealed a pathogenic mutation (388G-->T) in both the mother and the son. The possible relationship between the observed congenital anomalies and EDS IV are discussed. We stress that DNA analysis of COL3A1 should be performed in all patients when there is a strong suspicion of EDS IV, despite negative findings in a collagen protein analysis. 相似文献
10.
A novel missense mutation in exon 3 of the COL4A5 gene associated with late-onset Alport syndrome 总被引:1,自引:0,他引:1
Alberto E. Turco Sandro Rossetti M. Olivia Biasi Gianfranco Rizzoni Laura Massella Niina H. Saarinen Allessandra Renieri Pier Franco Pignatti Mario De Marchi 《Clinical genetics》1995,48(5):261-263
We have identified a novel missense transition (362G→A) in exon 3 of the COL4A5 gene in a male patient with late-onset Alport syndrome. We used non-isotopic single strand conformation polymorphism, heteroduplex analysis, and automated DNA sequencing. The mutation changes a conserved glycine at codon 54 for an aspartic acid (Gly54Asp), which abolishes a BstNI site. Using restriction analysis, we identified the heterozygous carrier status in the two daughters of the proband. Our findings are in keeping with the hypothesis that slower progressive forms of Alport syndrome are more often associated with missense mutations rather than large deletions or frameshifts. This is the first mutation described in the N-terminus triple helical 7S domain of the COL4A5 gene in an Alport syndrome patient. 相似文献
11.
Elise Venable Dacre R. T. Knight Emily K. Thoreson Linnea M. Baudhuin 《American journal of medical genetics. Part C, Seminars in medical genetics》2023,193(2):147-159
Pathogenic variants in COL1A1 and COL1A2 are involved in osteogenesis imperfecta (OI) and, rarely, Ehlers-Danlos syndrome (EDS) subtypes and OI-EDS overlap syndromes (OIEDS1 and OIEDS2, respectively). Here we describe a cohort of 34 individuals with likely pathogenic and pathogenic variants in COL1A1 and COL1A2, 15 of whom have potential OIEDS1 (n = 5) or OIEDS2 (n = 10). A predominant OI phenotype and COL1A1 frameshift variants are present in 4/5 cases with potential OIEDS1. On the other hand, 9/10 potential OIEDS2 cases have a predominant EDS phenotype, including four with an initial diagnosis of hypermobile EDS (hEDS). An additional case with a predominant EDS phenotype had a COL1A1 arginine-to-cysteine variant that was originally misclassified as a variant of uncertain significance despite this type of variant being associated with classical EDS with vascular fragility. Vascular/arterial fragility was observed in 4/15 individuals (including one individual with an original diagnosis of hEDS), which underscores the unique clinical surveillance and management needs in these patients. In comparison to previously described OIEDS1/2, we observed differentiating features that should be considered to refine currently proposed criteria for genetic testing in OIEDS, which will be beneficial for diagnosis and management. Additionally, these results highlight the importance of gene-specific knowledge for informed variant classification and point to a potential genetic resolution (COL1A2) for some cases of clinically diagnosed hEDS. 相似文献
12.
Richards AJ; Yates JR; Williams R; Payne SJ; Pope FM; Scott JD; Snead MP 《Human molecular genetics》1996,5(9):1339-1343
Stickler syndrome (hereditary arthro-ophthalmopathy) is the commonest
inherited cause of retinal detachment and one of the commonest autosomal
dominant connective tissue dysplasias. There is clinical and locus
heterogeneity with about two thirds of families linked to the gene encoding
type II procollagen (COL2A1). Families with Sticklers syndrome type 1 have
a characteristic congenital vitreous anomaly and are linked without
recombination to markers at the COL2A1 locus. In contrast families with the
type 2 variety have a different vitreo- retinal phenotype and are not
linked to the COL2A1 gene. Type XI collagen is a quantitatively minor
fibrillar collagen related to type V collagen and associated with the more
abundant type II collagen fibrils. A mutation in COL11A2, the gene for
alpha 2 (XI) procollagen, has recently been found in a family described as
having Stickler syndrome, although there was no ocular involvement. Here we
show for the first time that a family with the full Type 2 Stickler
syndrome including vitreous and retinal abnormalities is linked to the
COL11A1 gene and characterise the mutation as a Glycine to Valine
substitution at position 97 of the triple helical domain caused by a single
base G-- >T mutation. These results are the first to provide
confirmation that type XI collagen is an important structural component of
human vitreous. They also support previous work suggesting that mutations
in the genes encoding collagen XI can give rise to some manifestations of
Stickler syndrome, but of these, only mutations in COL11A1 will give the
full syndrome including the vitreo-retinal features.
相似文献
13.
A. Chico Luis Gallart Eugenia Mato Carmen Mayoral Jesus M. Martin-Campos Lluís Catasús Jose Rodriguez-Espinosa Xavier Matías-Guiu Francisco Blanco-Vaca Alberto de Leiva 《Journal of molecular medicine (Berlin, Germany)》1998,76(12):837-839
The autosomal dominant multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by neoplasia of parathyroids,
anterior pituitary, and gastrointestinal and pancreatic neuroendocrine tissues. Recently the gene responsible for the MEN1
syndrome has been identified on chromosome region 11q13. Most of the described mutations are nucleotide substitutions and
small deletions affecting exons 2 and 3, causing protein truncation. Only one mutation in exon 5 has been found, and this
corresponds to a MEN1 sporadic case. Small insertions are also rare. We studied a MEN1 family composed of five members, two
of whom were clinically affected. We found a new germline 1 basepair insertional mutation affecting the exon 5 of the MEN1
gene in the two members affected in this MEN1 family.
Received: 11 May 1998 / Accepted: 15 August 1998 相似文献
14.
Andreas Winterpacht Matthias Hilbert Ulrike Schwarze Stefan Mundlos Jürgen Spranger Bernhard Zabel 《Human mutation》1994,4(4):257-262
Osteoarthrosis represents a very common disease with heterogeneous etiology. In some pedigrees linkage of the condition with the type II collagen gene (COL2A1) has been established, but information on the underlying gene defect is still incomplete as only one mutation causing this phenotype has been identified. We analyzed the COL2A1 gene in a 27-year-old woman and her 47-year-old mother presenting with severe premature osteoarthrosis and X-ray signs compatible with mild spondyloepiphyseal dysplasia. Examination of the complete gene in both patients was done by amplification of all 54 exons, screening of the PCR products by SSCP-analysis, and subsequent sequencing. In mother and daughter a G to A transition at the 5′-end of exon 21 was detected, leading to a substitution of serine for glycine at position 274 of the triple helical domain. The mutation was not present in unaffected family members or in healthy control individuals. The autosomal dominant spondylarthropathies may represent the less severe entities of the clinical spectrum of type II collagenopathies. © 1994 Wiley-Liss, Inc. 相似文献
15.
Sanda Huljev Frkovi Ana Marija Slikovi Mia Toivonen Andrea Crkvenac Gregorek Ana utalo Majda Vrki Kirhmajer 《Croatian medical journal》2022,63(4):394
Due to life-threatening complications, vascular Ehlers-Danlos syndrome (vEDS) is the most severe form of EDS. Because the syndrome is associated with a shortened life expectancy and variable clinical presentation, diagnosis confirmed by genetic testing is crucial to determining appropriate treatment. Despite some distinguishing features, this rare disease often goes unrecognized. Apart from surgical or endovascular treatment of serious vascular complications, medical treatment based on celiprolol helps reduce arterial complications. We report on a case of vEDS in a young man who suffered several episodes of severe vascular complications. The diagnosis of vEDS was established based on clinical manifestations and confirmed by genetic testing. A novel heterozygous pathogenic variant in the COL3A1 gene was found. To our knowledge, this is the first case of vEDS caused by this variant.Vascular Ehlers-Danlos syndrome (vEDS), previously named type-IV EDS, is a rare genetic disorder of connective tissue, accounting for 5% of all EDS cases (1,2). It is characterized by serious complications such as spontaneous arterial dissections, aneurysms, ruptures, and gastrointestinal perforations, which begin in early adulthood. Reported median life expectancy is 51 years (2). The syndrome is caused by heterozygous mutations in the COL3A1 gene coding for type III procollagen, which result in the loss of mechanical strength of arteries and other hollow organs. The most common pathogenic variants in this syndrome are missense substitutions for glycine in the sequence of the collagen triple helix, and splice-site variants that lead to in-phase exon skipping (3). Herein, we report on a case of vEDS in a young man who suffered several episodes of severe vascular complications. In this patient, a novel heterozygous pathogenic variant in the COL3A1 gene was found. 相似文献
16.
Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome 总被引:5,自引:0,他引:5
Booms P Cisler J Mathews KR Godfrey M Tiecke F Kaufmann UC Vetter U Hagemeier C Robinson PN 《Clinical genetics》1999,55(2):110-117
The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32. 相似文献
17.
Giunta C Nuytinck L Raghunath M Hausser I De Paepe A Steinmann B 《American journal of medical genetics》2002,109(4):284-290
Skin hyperelasticity, tissue fragility with atrophic scars, and joint hypermobility are characteristic for the classical type of Ehlers-Danlos syndrome (EDS). The disease is usually inherited as an autosomal dominant trait; however, recessive mode of inheritance has been documented in tenascin-X-deficient EDS patients. Mutations in the genes coding for collagen alpha1(V) chain (COL5A1), collagen alpha2(V) chain (COL5A2), tenascin-X (TNX), and collagen alpha1(I) chain (COL1A1) have been characterized in patients with classical EDS, thus confirming the suspected genetic heterogeneity. Recently, we described a patient with severe classical EDS due to a Gly1489Glu substitution in the alpha1(V) triple-helical domain who was, in addition, heterozygous for a disease-modifying Gly530Ser substitution in the alpha1(V) NH(2)-terminal domain [Giunta and Steinmann, 2000: Am. J. Med. Genet. 90:72-79; Steinmann and Giunta, 2000: Am. J. Med. Genet. 93:342]. Here, we report on a 4-year-old boy with mild classical EDS, born to healthy consanguineous Turkish parents; the mother presented a soft skin, while the father had a normal thick skin. Ultrastructural analysis of the dermis revealed in the patient the typical "cauliflower" collagen fibrils, while in both parents variable moderate aberrations were seen. Mutation revealed the presence of a homozygous Gly530Ser substitution in the alpha1(V) collagen chains in the patient, while both parents were heterozygous for the same substitution. An additional mutation in either the COL5A1 and COL5A2 genes was excluded. Furthermore, haplotype analysis with polymorphic microsatellite markers excluded linkage to the genes coding for alpha3(V) collagen (COL5A3), tenascin-X (TNX), thrombospondin-2 (THBS2), and decorin (DCN). These new findings support further our previous hypothesis that the heterozygous Gly530Ser substitution is disease modifying and now suggest that in the homozygous state it is disease causing. 相似文献
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20.
Lysyl oxidase deficiency in Ehlers-Danlos syndrome type V. 总被引:6,自引:0,他引:6
N Di Ferrante R D Leachman P Angelini P V Donnelly G Francis A Almazan 《Connective tissue research》1975,3(1):49-53
Two maternal cousins affected by the X-linked form of Ehlers-Danlos syndrome have been observed. Both had congenital heart disease, "floppy valve syndrome", hernias, short stature, stretchable skin and moderate joint hypermobility. Both excreted normal amounts of urinary glycosaminoglycans, almost entirely represented by dermatan sulfate, whose degradation appeared to be inadequate. They also excreted large amounts of hydroxylysine glycosides and L-valyl-proline, considered to be products of degradation of collagen and elastin, respectively. Cultured skin fibroblasts of the propositus synthesized excessively soluble collagen and had a low lysyl oxidase activity. These findings suggest that the increased degradation of structural proteins may be secondary to the defective cross-linking processes caused by the enzymic defect. Addition of (+) catechin, a flavonoid, to the propositus's cultured fibroblasts decreased the abnormal solubility of their collagen. 相似文献