Novel mutation in the CHST14 gene causing musculocontractural type of Ehlers-Danlos syndrome.
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SUBMITTER: Sandal S
PROVIDER: S-EPMC6157554 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
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Novel mutation in the <i>CHST14</i> gene causing musculocontractural type of Ehlers-Danlos syndrome.
Sandal Sapna S Kaur Anupriya A Panigrahi Inusha I
BMJ case reports 20180923
Musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) is a recently recognised connective tissue disorder. MC-EDS is caused by homozygous or compound heterozygous mutation in the carbohydrate sulfotransferase 14 (<i>CHST14</i>) gene on chromosome 15q15. Herein, we report a case of a 3-year-old boy with MC-EDS in whom a novel mutation in the <i>CHST14</i> gene was discovered. Besides being the second report of this rare disorder from India, the child till 3 years has not had any bleeding te ...[more]
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Project description:The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.
| S-EPMC5115638 | biostudies-literature
Project description:Musculocontractural Ehlers-Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE). Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous (Chst14-/-) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.
| S-EPMC7017038 | biostudies-literature
Project description:Ehlers-Danlos syndrome (EDS) is a heritable connective tissue disorder characterized by a varying degree of skin hyperextensibility and joint hypermobility. EDS is classified into 13 subtypes according to the most recent classification. These subtypes are clinically and genetically heterogenous. The spondylodysplastic subvariety of EDS (spEDS) is caused by homozygous mutations in B4GALT7, B3GALT6 and SLC39A13. To date, 13 individuals with molecularly diagnosed SLC39A13-related spEDS have been reported. The spEDS caused by biallelic pathogenic SLC39A13 variants are characterized by short stature, protuberant eyes with bluish sclera, finely wrinkled palms, hypermobile joints, hyperextensible skin and characteristic radiological findings. Herein, we report a case of 7-year-old-female child with spEDS associated with novel homozygous (pathogenic/likely pathogenic) missense variation of the SLC39A13 gene.
| S-EPMC9885422 | biostudies-literature
Project description:Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a heritable connective tissue disorder characterized by multiple congenital malformations and progressive connective-tissue-fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral, ocular, and gastrointestinal systems. It is caused by pathogenic variants in the carbohydrate sulfotransferase 14 gene (mcEDS-CHST14) or in the dermatan sulfate epimerase gene (mcEDS-DSE). As gastrointestinal complications of mcEDS-CHST14, diverticula in the colon, small intestine, or stomach have been reported, which may lead to gastrointestinal perforation, here, we describe sisters with mcEDS-CHST14, who developed colonic perforation with no evidence of diverticula and were successfully treated through surgery (a resection of perforation site and colostomy) and careful postoperative care. A pathological investigation did not show specific abnormalities of the colon at the perforation site. Patients with mcEDS-CHST14 aged from the teens to the 30s should undergo not only abdominal X-ray photography but also abdominal computed tomography when they experience abdominal pain.
| S-EPMC10218258 | biostudies-literature
Project description:BackgroundMusculocontractural Ehlers-Danlos Syndrome (mcEDS) is a rare connective tissue disorder caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE), both of which result in defective dermatan sulfate biosynthesis. Forty-one patients with mcEDS-CHST14 and three patients with mcEDS-DSE have been described in the literature.MethodsClinical, molecular, and glycobiological findings in three additional patients with mcEDS-DSE were investigated.ResultsThree patients from two families shared craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia), skeletal features (pectus and spinal deformities, characteristic finger shapes, progressive talipes deformities), skin features (fine or acrogeria-like palmar creases), and ocular refractive errors. Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3. No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS.ConclusionMcEDS-DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS-CHST14. However, the burden of symptoms seems lower in patients with mcEDS-DSE.
| S-EPMC7216804 | biostudies-literature
Project description:Loss-of-function mutations in carbohydrate sulfotransferase 14 (CHST14) cause musculocontractural Ehlers-Danlos syndrome-CHST14 (mcEDS-CHST14), characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral and ocular system. The replacement of dermatan sulfate chains on decorin proteoglycan with chondroitin sulfate chains is proposed to lead to the disorganization of collagen networks in the skin. However, the pathogenic mechanisms of mcEDS-CHST14 are not fully understood, partly due to the lack of in vitro models of this disease. In the present study, we established in vitro models of fibroblast-mediated collagen network formation that recapacitate mcEDS-CHST14 pathology. Electron microscopy analysis of mcEDS-CHST14-mimicking collagen gels revealed an impaired fibrillar organization that resulted in weaker mechanical strength of the gels. The addition of decorin isolated from patients with mcEDS-CHST14 and Chst14-/- mice disturbed the assembly of collagen fibrils in vitro compared to control decorin. Our study may provide useful in vitro models of mcEDS-CHST14 to elucidate the pathomechanism of this disease.
| S-EPMC9957042 | biostudies-literature
Project description:Ehlers-Danlos syndrome type IV, the vascular type of Ehlers-Danlos syndromes (EDS), is an inherited connective tissue disorder defined by characteristic facial features (acrogeria) in most patients, translucent skin with highly visible subcutaneous vessels on the trunk and lower back, easy bruising, and severe arterial, digestive and uterine complications, which are rarely, if at all, observed in the other forms of EDS. The estimated prevalence for all EDS varies between 1/10,000 and 1/25,000, EDS type IV representing approximately 5 to 10% of cases. The vascular complications may affect all anatomical areas, with a tendency toward arteries of large and medium diameter. Dissections of the vertebral arteries and the carotids in their extra- and intra-cranial segments (carotid-cavernous fistulae) are typical. There is a high risk of recurrent colonic perforations. Pregnancy increases the likelihood of a uterine or vascular rupture. EDS type IV is inherited as an autosomal dominant trait that is caused by mutations in the COL3A1 gene coding for type III procollagen. Diagnosis is based on clinical signs, non-invasive imaging, and the identification of a mutation of the COL3A1 gene. In childhood, coagulation disorders and Silverman's syndrome are the main differential diagnoses; in adulthood, the differential diagnosis includes other Ehlers-Danlos syndromes, Marfan syndrome and Loeys-Dietz syndrome. Prenatal diagnosis can be considered in families where the mutation is known. Choriocentesis or amniocentesis, however, may entail risk for the pregnant woman. In the absence of specific treatment for EDS type IV, medical intervention should be focused on symptomatic treatment and prophylactic measures. Arterial, digestive or uterine complications require immediate hospitalisation, observation in an intensive care unit. Invasive imaging techniques are contraindicated. Conservative approach is usually recommended when caring for a vascular complication in a patient suffering from EDS type IV. Surgery may, however, be required urgently to treat potentially fatal complications.
| S-EPMC1971255 | biostudies-literature
Project description:Musculocontractural Ehlers-Danlos syndrome caused by mutations in the carbohydrate sulfotransferase 14 gene (mcEDS-CHST14) is a heritable connective tissue disorder characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral, and ocular systems. Progressive skeletal deformities are among the most frequent and serious complications affecting the quality of life and activities of daily living in patients. After establishing induced pluripotent stem cells (iPSCs) from cultured skin fibroblasts of three patients with mcEDS-CHST14, we generated a patient iPSC-based human osteogenesis model and performed an in vitro assessment of the phenotype and pathophysiology of skeletal deformities. Patient-derived iPSCs presented with remarkable downregulation of osteogenic-specific gene expression, less alizarin red staining, and reduced calcium deposition compared with wild-type iPSCs at each stage of osteogenic differentiation, including osteoprogenitor cells, osteoblasts, and osteocytes. These findings indicated that osteogenesis was impaired in mcEDS-CHST14 iPSCs. Moreover, the decrease in decorin (DCN) expression and increase in collagen (COL12A1) expression in patient-derived iPSCs elucidated the contribution of CHST14 dysfunction to skeletal deformities in mcEDS-CHST14. In conclusion, this disease-in-a-dish model provides new insight into the pathophysiology of EDS and may have the potential for personalized gene or drug therapy.
| S-EPMC10048181 | biostudies-literature
Project description:Classical Ehlers-Danlos syndrome (EDS) is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring. Mutations in type V collagen, a regulator of type I collagen fibrillogenesis, have been shown to underlie this type of EDS. However, to date, mutations have been found in only a limited number of patients, which suggests genetic heterogeneity. In this article, we report two unrelated patients with typical features of classical EDS, including excessive skin fragility, in whom we found an identical arginine-->cysteine substitution in type I collagen, localized at position 134 of the alpha1(I) collagen chain. The arginine residue is highly conserved and localized in the X position of the Gly-X-Y triplet. As a consequence, intermolecular disulfide bridges are formed, resulting in type I collagen aggregates, which are retained in the cells. Whereas substitutions of glycine residues in type I collagen invariably result in osteogenesis imperfecta, substitutions of nonglycine residues in type I collagen have not yet been associated with a human disease. In contrast, arginine-->cysteine substitutions in type II collagen have been identified in a variety of chondrodysplasias. Our findings show that mutations in other fibrillar collagens can be causally involved in classical EDS and point to genetic heterogeneity of this disorder.
| S-EPMC1288203 | biostudies-literature
Project description:We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud's phenomenon, and hypermobility. She was found to have a 6074A > T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classified as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient's symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome (EDS). At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X deficiency, but the variant identified in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A > T nucleotide transition in the TNXB gene may be classified as disease-causing for EDS due to tenascin-X deficiency.
| S-EPMC5363719 | biostudies-other