RESUMEN

The patient was a six-year-old boy with a history of musculocontractural Ehlers-Danlos syndrome (mcEDS). He presented to the emergency department after falling on the road the day before admission, which led to an increase in subcutaneous hematoma in his left lower leg and brief syncope. Initial blood tests revealed a decreased hemoglobin level of 8.1 g/dL (normal range: 14 g/dL). Contrast-enhanced CT showed a massive subcutaneous and intermuscular hematoma in the left thigh. He was diagnosed with hemorrhagic shock due to this extensive hemorrhage and was admitted to the ICU. The affected area was elevated, and hemostasis was achieved through compression. The swelling gradually improved, and he was discharged from the hospital on day 13 after admission. EDS is a systemic condition caused by genetic mutations affecting collagen and collagen-modifying enzymes. mcEDS is an extremely rare variant with a recently identified causative gene, characterized by abnormal connective tissue development and progressive fragility. Giant subcutaneous hematomas resulting from tissue fragility are serious complications of this disease, often occurring with minor trauma and sometimes leading to gradual hemorrhagic shock. Desmopressin nasal drops can be effective in preventing such hematomas. It is crucial to consider the risk of hemorrhagic shock from subcutaneous hemorrhage in patients with mcEDS, especially when repeated subcutaneous hematomas of unknown origin are observed.

RESUMEN

Previous studies have demonstrated that carbohydrate sulfotransferase family proteins (CHSTs) play a crucial role in the extracellular matrix structural constituent and cancer progression, however, the effect of CHSTs on gastric cancer is still superficial. To investigate these, our study seeks to provide a comprehensive understanding of CHSTs' expression, immune infiltration, and prognostic implications in gastric cancer, utilizing data from the TCGA, GEO and GTEx databases. Furthermore, we conducted experimental validation to elucidate the role of CHST14 specifically in gastric cancer. Our findings suggest that most CHSTs were highly expressed in gastric cancer. Gene copy number variations further indicated prevalent CHSTs amplification in gastric cancer, pointing to its potential relevance in disease progression. Intriguingly, we noted strong positive correlations between most CHSTs and immune cell infiltration. Importantly, most members of CHSTs were related to OS and PFI with gastric cancer, with particular emphasis on CHST14 and CHST9. Multifactorial regression analysis indicates that CHST14 is an independent prognostic factor influencing the overall survival of gastric cancer patients. In further experimental validation, our results demonstrate elevated expression of CHST14 in gastric cancer, and knocking down CHST14 inhibits gastric cancer cell proliferation, invasion, migration and EMT. Additionally, CHST14 may exert its function through the regulation of the Wnt pathway. In summary, our study comprehensively analyzes the hitherto undescribed role of CHSTs in gastric cancer through the analysis of multi-omics data. Importantly, we identify CHST14 as a pivotal promoter in the malignant progression of gastric cancer, offering potential targets for gastric cancer therapy.

RESUMEN

Musculocontractural Ehlers-Danlos syndrome (EDS) caused by pathogenic variants in CHST14 (mcEDS-CHST14) is a subtype of EDS characterized by multisystem malformations and progressive fragility-related manifestations. A recent international collaborative study showed that 55% of mcEDS-CHST14 patients had hearing loss (HL), more commonly of the high-frequency type. Here, we report the first systemic investigation of the otological features of patients with this disorder based on the world's largest cohort at Shinshu University Hospital. Nine patients [18 ears; four male and five female patients; mean age, 18 years old (range, 10-28)] underwent comprehensive otological evaluation: audiogram, distortion product otoacoustic emission (DPOAE) test, and tympanometry. The audiogram, available in all 18 ears, showed HL in eight patients (8/9, 89%) and in 14 ears (14/18, 78%): bilateral in six patients (6/9, 67%) and unilateral in two (2/9, 22%); mild in eight ears (8/18, 44%) and moderate in six (6/18, 33%); and high-frequency HL in five (5/18, 28%) and low-frequency HL in five (5/18, 28%). An air-bone gap was detected in one ear (1/18, 6%). DPOAE was available in 13 ears, with the presence of a response in five (5/13, 38%) and the absence in eight (8/13, 62%), including in three ears of normal hearing. Tympanometry results were available in 12 ears: Ad type in nine (9/12, 75%) and As type in one (1/12, 8.3%). Patients with mcEDS-CHST14 had a high prevalence of HL, typically sensorineural and bilateral, with mild to moderate severity, of high-frequency or low-frequency type, and sometimes with no DPOAE response. The pathophysiology underlying HL might be complex, presumably related to alterations of the tectorial membrane and/or the basilar membrane of Corti associated with disorganized collagen fibril networks. Regular and careful check-ups of hearing using multiple modalities are recommended for mcEDS-CHST14 patients.

Asunto(s)

Sordera , Síndrome de Ehlers-Danlos , Adolescente , Femenino , Humanos , Masculino , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Matriz Extracelular/patología , Piel/patología , Sulfotransferasas/genética

RESUMEN

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.

Asunto(s)

Divertículo , Síndrome de Ehlers-Danlos , Adolescente , Humanos , Sulfotransferasas/genética , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/cirugía , Piel/patología , Proteínas de Unión al ADN/genética , Divertículo/patología

RESUMEN

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.

Asunto(s)

Síndrome de Ehlers-Danlos , Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Actividades Cotidianas , Osteogénesis/genética , Calidad de Vida , Sulfotransferasas/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo

RESUMEN

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.

Asunto(s)

Síndrome de Ehlers-Danlos , Sulfotransferasas , Animales , Ratones , Decorina , Sulfotransferasas/genética , Síndrome de Ehlers-Danlos/genética , Matriz Extracelular/patología , Colágeno

RESUMEN

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 (CHST14) (mcEDS-CHST14) or dermatan sulfate epimerase (DSE) (mcEDS-DSE). These mutations induce loss of enzymatic activity in D4ST1 or DSE and disrupt dermatan sulfate (DS) biosynthesis. The depletion of DS causes the symptoms of mcEDS, such as multiple congenital malformations (e.g., adducted thumbs, clubfeet, and craniofacial characteristics) and progressive connective tissue fragility-related manifestations (e.g., recurrent dislocations, progressive talipes or spinal deformities, pneumothorax or pneumohemothorax, large subcutaneous hematomas, and/or diverticular perforation). Careful observations of patients and model animals are important to investigate pathophysiological mechanisms and therapies for the disorder. Some independent groups have investigated Chst14 gene-deleted (Chst14-/-) and Dse-/- mice as models of mcEDS-CHST14 and mcEDS-DSE, respectively. These mouse models exhibit similar phenotypes to patients with mcEDS, such as suppressed growth and skin fragility with deformation of the collagen fibrils. Mouse models of mcEDS-CHST14 also show thoracic kyphosis, hypotonia, and myopathy, which are typical complications of mcEDS. These findings suggest that the mouse models can be useful for research uncovering the pathophysiology of mcEDS and developing etiology-based therapy. In this review, we organize and compare the data of patients and model mice.

Asunto(s)

Dermatán Sulfato , Síndrome de Ehlers-Danlos , Animales , Ratones , Sulfotransferasas/genética , Síndrome de Ehlers-Danlos/genética , Piel , Matriz Extracelular

RESUMEN

A 36-year-old male with congenital equinovarus deformity was admitted to the hospital due to worsen deformity. He was known to have ear perforation in childhood. After hospitalization, he received equinovarus correction surgery, fourth toe osteotomy, and external fixation for right foot during the procedure. During his hospital stay, the patient has been treated with multiple gastrointestinal perorations, accompanied with multiple organ dysfunction and fragile soft tissues. During his in-hospital stay, multiple organ dysfunctions were observed, including the heart, kidney, liver, and intestines. In order to identify the mutation site, whole-exome sequencing (WES) was performed, and further verified with Sanger sequencing analysis in this patient. One-site mutation located at CHST14 [c.883_884del, p (Phe295Cysfs*5)] was identified in this patient, whereas this mutation was not observed in other 100 healthy controls. Also, this variant has not been reported in public databases (ExAC and gnomAD). Our report showed that unanticipated multiple tissue deformation observed the musculocontractural EDS patient was caused by mutation located at CHST14 [c.883_884del, p (Phe295Cysfs*5)] induced truncated CHST14 protein.

RESUMEN

Living with an undiagnosed medical condition places a tremendous burden on patients, their families, and their healthcare providers. The Undiagnosed Diseases Program (UDP) was established at the National Institutes of Health (NIH) in 2008 with the primary goals of providing a diagnosis for patients with mysterious conditions and advancing medical knowledge about rare and common diseases. The program reviews applications from referring clinicians for cases that are considered undiagnosed despite a thorough evaluation. Those that are accepted receive clinical evaluations involving deep phenotyping and genetic testing that includes exome and genomic sequencing. Selected candidate gene variants are evaluated by collaborators using functional assays. Since its inception, the UDP has received more than 4500 applications and has completed evaluations on nearly 1300 individuals. Here we present six cases that exemplify the discovery of novel disease mechanisms, the importance of deep phenotyping for rare diseases, and how genetic diagnoses have led to appropriate treatment. The creation of the Undiagnosed Diseases Network (UDN) in 2014 has substantially increased the number of patients evaluated and allowed for greater opportunities for data sharing. Expansion to the Undiagnosed Diseases Network International (UDNI) has the possibility to extend this reach even farther. Together, networks of undiagnosed diseases programs are powerful tools to advance our knowledge of pathophysiology, accelerate accurate diagnoses, and improve patient care for patients with rare conditions.

Asunto(s)

Enfermedades no Diagnosticadas , Exoma , Humanos , National Institutes of Health (U.S.) , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Estados Unidos , Uridina Difosfato

RESUMEN

Background: Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare heritable connective tissue disease with various symptoms. The diagnosis of mcEDS is difficult because of the large overlap of clinical symptoms between different EDS subtypes. Methods: We performed karyotype analysis, gene copy number variation detection, whole-exome sequencing, and Sanger sequencing to reveal the underlying genetic etiology of a fetus with structural abnormalities in feet and kidneys. Results: A likely pathogenic mutation [NM_130468.3 c.958C>T (p.Arg320*)] and an uncertain significance mutation [NM_130468.3 c.896A>G (p.Tyr299Cys)] were identified in the carbohydrate sulfotransferase 14 (CHST14) gene by whole-exome sequencing and validated by Sanger sequencing. Conclusion: The two identified mutations appear highly likely to be the genetic causes of the fetal structural abnormalities.

RESUMEN

Ehlers-Danlos syndrome (EDS) is a genetically and clinically heterogeneous group of connective tissue disorders that typically present with skin hyperextensibility, joint hypermobility, and tissue fragility. The major cause of EDS appears to be impaired biosynthesis and enzymatic modification of collagen. In this chapter, we discuss two types of EDS that are associated with proteoglycan abnormalities: spondylodysplastic EDS and musculocontractural EDS. Spondylodysplastic EDS is caused by pathogenic variants in B4GALT7 or B3GALT6, both of which encode key enzymes that initiate glycosaminoglycan synthesis. Musculocontractural EDS is caused by mutations in CHST14 or DSE, both of which encode enzymes responsible for the post-translational biosynthesis of dermatan sulfate. The clinical and molecular characteristics of both types of EDS are described in this chapter.

Asunto(s)

Síndrome de Ehlers-Danlos , Colágeno , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Galactosiltransferasas/genética , Glicosaminoglicanos , Humanos , Mutación , Sulfotransferasas

RESUMEN

Carbohydrate sulfotransferase 14 (CHST14) encodes dermatan 4-O-sulfotransferase 1, a critical enzyme for dermatan sulfate (DS) biosynthesis. Musculocontractural Ehlers-Danlos syndrome (mcEDS) is associated with biallelic pathogenic variants of CHST14 and is characterized by malformations and manifestations related to progressive connective tissue fragility. We identified myopathy phenotypes in Chst14-deficient mice using an mcEDS model. Decorin is a proteoglycan harboring a single glycosaminoglycan chain containing mainly DS, which are replaced with chondroitin sulfate (CS) in mcEDS patients with CHST14 deficiency. We studied the function of decorin in the skeletal muscle of Chst14-deficient mice because decorin is important for collagen-fibril assembly and has a myokine role in promoting muscle growth. Although decorin was present in the muscle perimysium of wild-type (Chst14+/+ ) mice, decorin was distributed in the muscle perimysium as well as in the endomysium of Chst14-/- mice. Chst14-/- mice had small muscle fibers within the spread interstitium; however, histopathological findings indicated milder myopathy in Chst14-/- mice. Myostatin, a negative regulator of protein synthesis in the muscle, was upregulated in Chst14-/- mice. In the muscle of Chst14-/- mice, decorin was downregulated compared to that in Chst14+/+ mice. Chst14-/- mice showed altered cytokine/chemokine balance and increased fibrosis, suggesting low myogenic activity in DS-deficient muscle. Therefore, DS deficiency in mcEDS causes pathological localization and functional abnormalities of decorin, which causes disturbances in skeletal muscle myogenesis.

RESUMEN

Loss-of-function variants in CHST14 cause a dermatan 4-O-sulfotransferase deficiency named musculocontractural Ehlers-Danlos syndrome-CHST14 (mcEDS-CHST14), resulting in complete depletion of the dermatan sulfate moiety of decorin glycosaminoglycan (GAG) chains, which is replaced by chondroitin sulfate. Recently, we uncovered structural alteration of GAG chains in the skin of patients with mcEDS-CHST14. Here, we conducted the first systematic investigation of Chst14 gene-deleted homozygote (Chst14-/-) mice. We used skin samples of wild-type (Chst14+/+) and Chst14-/- mice. Mechanical fragility of the skin was measured with a tensile test. Pathology was observed using light microscopy, decorin immunohistochemistry and electron microscopy (EM) including cupromeronic blue (CB) staining. Quantification of chondroitin sulfate and dermatan sulfate was performed using enzymatic digestion followed by anion-exchange HPLC. In Chst14-/- mice, skin tensile strength was significantly decreased compared with that in Chst14+/+ mice. EM showed that collagen fibrils were oriented in various directions to form disorganized collagen fibers in the reticular layer. Through EM-based CB staining, rod-shaped linear GAG chains were found to be attached at one end to collagen fibrils and protruded outside of the fibrils, in contrast to them being round and wrapping the collagen fibrils in Chst14+/+ mice. A very low level of dermatan sulfate disaccharides was detected in the skin of Chst14-/- mice by anion-exchange chromatography. Chst14-/- mice, exhibiting similar abnormalities in the GAG structure of decorin and collagen networks in the skin, could be a reasonable model for skin fragility of patients with mcEDS-CHST14, shedding light on the role of dermatan sulfate in maintaining skin strength.

Asunto(s)

Síndrome de Ehlers-Danlos/genética , Piel/metabolismo , Sulfotransferasas/genética , Animales , Síndrome de Ehlers-Danlos/patología , Ratones , Ratones Noqueados , Sulfotransferasas/deficiencia , Sulfotransferasas/metabolismo

RESUMEN

Ehlers-Danlos syndromes (EDSs) are heterogeneous group of heritable connective tissue disorders characterized by joint and skin hyperextensibility as well as fragility of various organs. Recently, we described a new type of EDS, musculocontractual EDS (mcEDS-CHST14), caused by pathogenic variants of the carbohydrate sulfotransferase 14 (CHST14) gene mutation. B6;129S5-Chst14tm1Lex/Mmucd (B6;129-Chst14 KO) mice are expected to be an animal model of mcEDS-CHST14. However, >90% of B6;129-Chst14 KO homozygous (B6;129-Chst14-/-) mice show perinatal lethality. Therefore, improvement of the birth rate of Chst14-/- mice is needed to clarify the pathophysiology of mcEDS-CHST14 using this animal model. Some B6;129-Chst14-/- embryos had survived at embryonic day 18.5 in utero, suggesting that problems with delivery and/or childcare may cause perinatal lethality. However, in vitro fertilization and egg transfer did not improve the birth rate of the mice. A recent report showed that backcrossing to C57BL/6 strain induces perinatal death of all Chst14-/- mice, suggesting that genetic background influences the birthrate of these mice. In the present study, we performed backcrossing of B6;129-Chst14 KO mice to a BALB/c strain, an inbred strain that shows lower risks of litter loss than C57BL/6 strain. Upon backcrossing 1 to 12 times, the birth rate of Chst14-/- mice was improved with a birth rate of 6.12-18.64%. These results suggest that the genetic background influences the birth rate of Chst14-/- mice. BALB/c congenic Chst14-/- (BALB.Chst14-/-) mice may facilitate investigation of mcEDS-CHST14. Furthermore, backcrossing to an appropriate strain may contribute to optimizing animal experiments.

Asunto(s)

Tasa de Natalidad , Modelos Animales de Enfermedad , Síndrome de Ehlers-Danlos , Eliminación de Gen , Endogamia/métodos , Ratones Endogámicos BALB C/genética , Ratones Endogámicos C57BL/genética , Ratones Noqueados/genética , Sulfotransferasas/genética , Animales , Femenino , Masculino

RESUMEN

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is an autosomal recessive condition characterized by distinct craniofacial features, multisystem congenital malformations and progressive fragility of connective tissues. It is caused by pathogenic variants in CHST14 and DSE genes. There are three reports of pathogenic variants in DSE in four mcEDS patients. In this study we provide clinical and molecular presentation of two new patients with DSE related mcEDS. Analysing clinical exome data, a homozygous pathogenic DSE variant, c.1150_1157del p.(Pro384Trpfs*9), was identified in a 32 year old man with bilateral congenital talipes equinovarus, characteristic facial features, myopia, hyperextensible skin at the elbows, significant palmar wrinkling, bilateral inguinal hernias and chronic leg, back and joint pain. Electron microscopical examination of skin biopsy showed changes consistent with mild compensatory elastic fibre hypertrophy and mildly loose collagen bundles. The variant is predicted to result in a frameshift and introduction of a premature termination codon in the final exon of the DSE gene, anticipated to lead to the loss of approximately 60% of the normal reading frame. The second patient has a phenotype consistent with previously reported cases of DSE associated musculocontractural EDS. A novel homozygous missense DSE variant of uncertain clinical significance was detected. This case study further delineates the DSE associated mcEDS phenotype and illustrates absence of major cutaneous, cardiovascular, renal and respiratory features, which supports previous suggestions that patients with DSE associated mcEDS present with a milder phenotype compared to those with CHST14 mutations.

Asunto(s)

Antígenos de Neoplasias/genética , Contractura/patología , Proteínas de Unión al ADN/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Mutación , Proteínas de Neoplasias/genética , Adulto , Variación Biológica Poblacional , Contractura/genética , Humanos , Masculino , Fenotipo

RESUMEN

Chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans (PGs) are major extracellular matrix (ECM) components of the central nervous system (CNS). A large body of evidence has shown that CSPGs/DSPGs play critical roles in neuronal growth, axon guidance, and plasticity in the developing and mature CNS. It has been proposed that these PGs exert their function through specific interaction of CS/DS chains with its binding partners in a manner that depends on the sulfation patterns of CS/DS. It has been reported that dermatan 4-O-sulfotransferase-1 (Chst14/D4st1) specific for DS, but not chondroitin 4-O-sulfotransferase-1 (Chst11/C4st1) specific for CS, regulates proliferation and neurogenesis of neural stem cells (NSCs), indicating that CS and DS play distinct roles in the self-renewal and differentiation of NSCs. However, it remains unknown whether specific sulfation profiles of DS has any effect on CNS plasticity. In the present study, Chst14/D4st1-deficient (Chst14 -/-) mice was employed to investigate the involvement of DS in synaptic plasticity. First, behavior study using Morris Water Maze (MWM) showed that the spatial learning and memory of Chst14 -/- mice was impaired when compared to their wild type (WT) littermates. Corroborating the behavior result, long-term potentiation (LTP) at the hippocampal CA3-CA1 connection was reduced in Chst14 -/- mice compared to the WT mice. Finally, the protein levels of N-Methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, postsynaptic density 95 (PSD95), growth associated protein 43 (GAP-43), synaptophysin (SYN) and N-ethylmaleimide sensitive factor (NSF) which are important in synaptic plasticity were examined and Chst14/D4st1 deficiency was shown to significantly reduce the expression of these proteins in the hippocampus. Further studies revealed that Akt/mammalian target rapamycin (mTOR) pathway proteins, including protein kinase B (p-Akt), p-mTOR and p-S6, were significantly lower in Chst14 -/- mice, which might contribute to the decreased protein expression. Together, this study reveals that specific sulfation of DS is critical in synaptic plasticity of the hippocampus and learning and memory, which might be associated with the changes in the expression of glutamate receptors and other synaptic proteins though Akt/mTOR pathway.

RESUMEN

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.

Asunto(s)

Antígenos de Neoplasias/genética , Proteínas de Unión al ADN/genética , Síndrome de Ehlers-Danlos/patología , Proteínas de Neoplasias/genética , Sulfotransferasas/genética , Sulfatos de Condroitina/metabolismo , Dermatán Sulfato/metabolismo , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Femenino , Humanos , Masculino , Linaje , Fenotipo

RESUMEN

Musculocontractural Ehlers-Danlos syndrome (mcEDS) due to CHST14/D4ST1 deficiency (mcEDS-CHST14) is a recently delineated type of EDS caused by biallelic loss-of-function mutations in CHST14, which results in the depletion of dermatan sulfate (DS). Clinical characteristics of mcEDS-CHST14 consist of multiple malformations and progressive fragility-related manifestations, including skin hyperextensibility and fragility. Skin fragility is suspected to result from the impaired assembly of collagen fibrils caused by alteration of the glycosaminoglycan (GAG) chain of decorin-proteoglycan (PG) from DS to chondroitin sulfate (CS). This systematic investigation of the skin pathology of patients with mcEDS-CHST14 comprised both immunostaining of decorin and transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains. Collagen fibrils were dispersed in the affected papillary to reticular dermis; in contrast, they were regularly and tightly assembled in controls. Moreover, the fibrils exhibited a perpendicular arrangement to the affected epidermis, whereas fibrils were parallel to control epidermis. Affected GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils; in contrast, those of controls were curved, maintaining close contact with attached collagen fibrils. This is the first observation of compositional alteration, from DS to CS, of GAG side chains, which caused structural alteration of GAG side chains and resulted in spatial disorganization of collagen networks; this presumably disrupted the ring-mesh structure of GAG side chains surrounding collagen fibrils. McEDS-CHST14 provides a critical example of the importance of DS in GAG side chains of decorin-PG during assembly of collagen fibrils in maintenance of connective tissues.

Asunto(s)

Colágeno/metabolismo , Síndrome de Ehlers-Danlos , Glicosaminoglicanos/metabolismo , Piel/metabolismo , Piel/ultraestructura , Sulfotransferasas/genética , Adolescente , Adulto , Secuencia de Carbohidratos , Estudios de Casos y Controles , Niño , Preescolar , Colágeno/química , Colágeno/ultraestructura , Decorina/metabolismo , Dermatán Sulfato/metabolismo , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/patología , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Femenino , Glicosaminoglicanos/química , Glicosaminoglicanos/ultraestructura , Humanos , Masculino , Conformación Molecular , Mutación , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Piel/patología , Relación Estructura-Actividad , Sulfotransferasas/metabolismo , Adulto Joven

RESUMEN

Musculocontractural Ehlers-Danlos syndrome caused by mutations in CHST14 (mcEDS-CHST14) is a recently delineated disorder, characterized by craniofacial, skeletal, visceral, and ocular malformations; and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Spinal lesions, though one of the most serious complications, have not been investigated systematically. In this study, we report detailed and comprehensive information about spinal lesions of 12 patients with a mean age at the first visit of 13.4 years. Eight patients (66.7%) had scoliosis with a Cobb angle ≥10°, including one with severe scoliosis with a Cobb angle ≥45°. Five patients (41.7%) had kyphosis at the thoracolumbar junction with a kyphotic angle ≥20°. Three patients (25%) developed severe thoracolumbar kyphosis with a kyphotic angle ≥50° accompanied by thoracic lordosis with a wedge-like vertebral deformity and anterior vertebral osteophyte at the thoracolumbar junction, and two of them underwent surgical correction: complicated by fistula formation in one and performed safely and effectively through two-staged operation in the other. Six patients (50.0%) had cervical kyphosis, all of whom except one had kyphosis ≥20° at the thoracolumbar level. Two patients (16.7%) had atlantoaxial subluxation, and 10 patients (83.3%) had cervical vertebral malformations. Patients with mcEDS-CHST14 are susceptible to develop scoliosis, thoracolumbar kyphosis, and cervical kyphosis; and are recommended to have regular surveillance including total spine radiology. The present findings also suggest the critical role of dermatan sulfate in the development and maintenance of the spine.

Asunto(s)

Síndrome de Ehlers-Danlos/enzimología , Médula Espinal/patología , Sulfotransferasas/deficiencia , Adolescente , Adulto , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/patología , Niño , Preescolar , Síndrome de Ehlers-Danlos/diagnóstico por imagen , Femenino , Humanos , Masculino , Médula Espinal/diagnóstico por imagen , Médula Espinal/cirugía , Sulfotransferasas/metabolismo , Tomografía Computarizada por Rayos X , Adulto Joven

RESUMEN

Collagen is one of the most important components of the extracellular matrix that is involved in the strength of tissues, cell adhesion and cell proliferation. Mutations in several collagen and post-translational modification enzyme genes cause Ehlers-Danlos syndrome (EDS) characterized by joint and skin hyperextensibility as well as fragility of various organs. Carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase-1 (CHST14/D4ST1) is a critical enzyme for biosynthesis of dermatan sulfate, a side chain of various proteoglycans including biglycan that regulates collagen fibrils through their interaction. Mutations in CHST14 were found to cause a new form of EDS, named musculocontractural type EDS (mcEDS-CHST14). Large subcutaneous hematomas are one of the most serious complications accompanied by decreased quality of life and potential lethality. In this study, Chst14 gene-deleted mice were expected to be an animal model of the vascular abnormalities of mcEDS-CHST14. However, only limited numbers of adult mice were generated because of perinatal lethality in most Chst14 gene-deleted homozygote (Chst14-/-) mice. Therefore, we investigated the placentas of these fetuses. The placentas of Chst14-/- fetuses showed a reduced weight, alterations in the vascular structure, and ischemic and/or necrotic-like changes. Electron microscopy demonstrated an abnormal structure of the basement membrane of capillaries in the placental villus. These findings suggest that Chst14 is essential for placental vascular development and perinatal survival of fetuses. Furthermore, placentas of Chst14-/- fetuses could be a useful model for vascular manifestations in mcEDS-CHST14, such as the large subcutaneous hematomas.

Asunto(s)

Síndrome de Ehlers-Danlos/genética , Placenta/patología , Sulfotransferasas/genética , Animales , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Colágeno/metabolismo , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/patología , Femenino , Muerte Fetal , Masculino , Ratones , Placenta/irrigación sanguínea , Placenta/metabolismo , Embarazo , Sulfotransferasas/metabolismo