Actins ; genetics ; Adolescent ; Cardiomyopathy, Dilated ; genetics ; Child ; Child, Preschool ; Desmin ; genetics ; Female ; Humans ; Infant ; Male ; Mutation

OBJECTIVE: To explore the clinical characteristics and genetic variant of a patient with desminopathy manifesting with atypical symptoms. METHODS: A patient who was admitted to the Department of Neurology of Jing'an District Central Hospital on February 24, 2021 was selected as the study subject. Clinical data, laboratory tests, muscle pathology, muscle magnetic resonance imaging (MRI) and genetic testing of the patient were retrospectively analyzed. RESULTS: The patient had developed myalgia after lower limb activity, and gradually developed asymmetrical muscle weakness and atrophy of the lower limbs. Cardiac examination revealed atrioventricular block and decreased left ventricular diastolic function. Muscle MRI showed that semitendinosus, sartorius, gracilis, fibula, gastronemius and supinator muscles were selectively involved at the early stage. Muscle biopsy confirmed pathological changes of desmin positive myofibrils. Genetic testing revealed that the patient has harbored a c.1024A>G (p.n342d) missense variant in exon 6 of the DES gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS4_moderate+PM2_supporting+PP3_moderate+PP1). CONCLUSION Desmin disease has a great clinical heterogeneity. Postexercise myalgia of lower limbs is a rare clinical phenotype. For patients harboring the c.1024A>G (p.n342d) variant of the DES gene, in addition to semitendinosus and fibula, Cardiac involvement is relatively insidious and easy to be ignored in clinic. Timely muscle MRI, muscle biopsy and gene detection will help the early diagnosis of the disease.
Humans ; Myalgia/genetics* ; Desmin/genetics* ; Retrospective Studies ; Muscle, Skeletal ; Lower Extremity ; Mutation

PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract. Recent studies have revealed much of the biological and genetics underpinning GISTs. METHODS: KIT, PDGFRA, NF2 and GPHN mutations were examined by PCR-SSCP and DNA sequencing. Immunohistochemical analyses of CD117, CD34, SMA, S-100 and desmin were performed in 11 GISTs cases, and each tumor classified as being either very low, low, intermediate or high risk. RESULTS: Mutation in exon 11 of KIT was identified in 6 of the 11 GISTs, but mutations in exon 9, 13 and 17 of KIT were not detected. Three cases lacking KIT mutations showed PDGFRA mutations. No NF2 mutations were detected. GPHN gene mutation in exon 1 was identified in one case, which showed a simple point mutation in exon 11 of KIT. In a correlation between the mutation types and risk of aggressive behavior, four tumors involved multiple ( >2 codons) KIT mutations and one showed a point mutation of KIT plus a GPHN mutation were high risk, but one tumor with a point mutation of KIT showed a low risk. Three tumors having a PDGFRA mutation were of intermediate or very low risk. CONCLUSION: Mutations at exon 9, 13 or 17 of KIT and a NF2 mutation are considered rare in sporadic GIST. KIT and PDGFRA mutations appeared to be alternatives. A GPHN mutation occurring with a KIT mutation may be a secondary change in the pathogenesis of GIST, as the KIT mutation is a major event in GIST. KIT mutant GIST may have a poorer prognosis than PDGFRA mutant GIST.
Desmin ; Exons ; Gastrointestinal Stromal Tumors* ; Gastrointestinal Tract ; Genetics ; Point Mutation ; Prognosis ; Sequence Analysis, DNA

BACKGROUND: Desminopathy, a hereditary myofibrillar myopathy, mainly results from the desmin gene (DES) mutations. Desminopathy involves various phenotypes, mainly including different cardiomyopathies, skeletal myopathy, and arrhythmia. Combined with genotype, it helps us precisely diagnose and treat for desminopathy. METHODS: Sanger sequencing was used to characterize DES variation, and then a minigene assay was used to verify the effect of splice-site mutation on pre-mRNA splicing. Phenotypes were analyzed based on clinical characteristics associated with desminopathy. RESULTS: A splicing mutation (c.735+1G>T) in DES was detected in the proband. A minigene assay revealed skipping of the whole exon 3 and transcription of abnormal pre-mRNA lacking 32 codons. Another affected family member who carried the identical mutation, was identified with a novel phenotype of desminopathy, non-compaction of ventricular myocardium. There were 2 different phenotypes varied in cardiomyopathy and skeletal myopathy among the 2 patients, but no significant correlation between genotype and phenotype was identified. CONCLUSIONS We reported a novel phenotype with a splicing mutation in DES, enlarging the spectrum of phenotype in desminopathy. Molecular studies of desminopathy should promote our understanding of its pathogenesis and provide a precise molecular diagnosis of this disorder, facilitating clinical prevention and treatment at an early stage.
Animals ; Asian Continental Ancestry Group ; Cardiomyopathies ; genetics ; pathology ; Desmin ; genetics ; Electrocardiography ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Muscular Dystrophies ; genetics ; pathology ; Mutation ; genetics ; Pedigree ; Phenotype

OBJECTIVETo investigate the clinical and myopathological characteristics and desmin mutations in patients with desminopathy associated cardiomyopathy from 5 Chinese families.

METHODSThirty-six individuals (18 male, 18 female) were from 4 autosomal dominant inherited families and 1 sporadic case. Nineteen patients manifested myopathy followed by cardiomyopathy; 13 patients presented with isolated cardiomyopathy; 1 patient had isolated myopathy; 3 patients died of cardiac diseases without detailed clinical information. Out of the 23 patients underwent electrocardiogram examinations, 20 patients showed kinds of abnormalities in cardiac conduction block. Echocardiogram revealed dilated cardiomyopathy in one case, hypertrophic cardiomyopathy in one case, and restrictive cardiomyopathy in two cases. Muscle specimens from 7 different patients were performed for histological, immunohistochemistry and ultrastructural examinations. All exons of the desmin gene were screened in 21 patients, 17 asymptomatic family individuals and 50 Chinese controls.

RESULTSMuscle biopsies revealed multiple proteins aggregated in muscle fibers, also supported by immunostaining and electroscopic examinations. Five novel heterogeneous mutations were identified in 4 families and one sporadic case.

CONCLUSIONSNovel mutations of desmin gene were linked with cardiomyopathy in patients from 5 Chinese families with desminopathy.

Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; Cardiomyopathies ; diagnosis ; genetics ; DNA Mutational Analysis ; Desmin ; genetics ; Exons ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree

OBJECTIVETo study the expression of TGF-beta(1)vimentin and desmin in the renal cortex of diabetic rats induced by STZ.

METHODSDiabetes was induced in 24 male SD rats by single intraperitoneal injection of 1.0%STZ (70 mg/kg). Twenty-four age, weight and sex matched SD rats were used as controls. The expression of TGF-beta(1),vimentin and desmin mRNA in the renal cortex were detected by RT-PCR on the 3rd, the 7th, the 14th and the 30th day after the DM rat model established.

RESULT(1)The expression of TGF-beta(1), vimentin mRNA in the renal cortex of diabetic rats gradually increased respectively from the 7th day and the 14th day after the model established, and the expressive intensity was significantly greater than that in controls (P<0.05 or P<0.01). However,the expression of desmin mRNA in the renal cortex of diabetic rats gradually decreased from the 14th day after the model established, and the expressive intensity was significantly less than that in controls (P<0. 05 or P<0.01). (2) The expression of TGF-beta(1)mRNA correlated positively to that of vimentin mRNA (r 0.740 P=0.000), while the expression of desmin mRNA correlated negatively to that of TGF-beta(1)mRNA (r 0.695 P=0.000) and to that of vimentin mRNA (r 0.591 P=0.002).

CONCLUSIONThe expression of renal cortical TGF-beta(1) and vimentin mRNA gradually increase while the expression of desmin mRNA gradually decrease during the first month of the diabetic model established suggest TGF-beta(1) may play a role in the transformation of renal tubular epithelial cells into fibroblast during the progressive interstitial fibrosis of diabetic nephropathy.

Animals ; Desmin ; genetics ; Diabetes Mellitus, Experimental ; metabolism ; Kidney Cortex ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Transforming Growth Factor beta ; genetics ; Transforming Growth Factor beta1 ; Vimentin ; genetics

BACKGROUNDArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiac disease predominantly caused by mutations in desmosomal protein genes. Previous genetic analyses of the Chinese ARVC population are limited to small size and restriction to a single gene. This study was aimed to investigate the genotype in a large series of Chinese patients with ARVC through comprehensively screening nine ARVC-causing genes.

METHODSA total of 100 unrelated ARVC patients and 300 age, gender and ethnicity matched healthy controls were genetically tested with multiplexing targeted resequencing for nine previously reported ARVC-causing genes, including plakophilin-2, desmoplakin, desmoglein-2, desmocollin-2, plakoglobin, transforming growth factor beta-3, transmembrane protein 43, desmin and Lamin A/C.

RESULTSFifty-nine mutations were identified in 64% of the patients, among which, 93% were located in desmosomal protein genes. Plakophilin-2 mutations accounted for 54% of the total and 58% of the desmosomal mutations, with a truncating mutation type making up about 2/3 of the plakophilin-2 mutations. Only four mutations were found in non-desmosomal genes; two in transmembrane protein 43 and two in transforming growth factor beta-3. Two of them (one of each gene) appeared as single missense mutations. No mutation was identified in desmin or Lamin A/C. Multiple mutations were found in 23% of the patients, with plakophilin-2 being found in 57% of the multi-mutation carriers.

CONCLUSIONSPlakophilin-2 was the most common gene mutation that was identified in Chinese ARVC patients. Non-desmosomal genes should be added to desmosomal protein genes when performing molecular genetic screening in patients with suspected ARVC.

Adult ; Arrhythmogenic Right Ventricular Dysplasia ; genetics ; metabolism ; Asian Continental Ancestry Group ; Desmin ; genetics ; Desmoglein 2 ; genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Plakophilins ; genetics ; Young Adult ; gamma Catenin ; genetics

Animals ; Desmin ; analysis ; genetics ; Female ; Immunohistochemistry ; Intermediate Filament Proteins ; analysis ; genetics ; Kidney Glomerulus ; chemistry ; Nephrosis ; metabolism ; Nerve Tissue Proteins ; analysis ; genetics ; Nestin ; Podocytes ; chemistry ; RNA, Messenger ; analysis ; Rats ; Rats, Inbred WKY ; Vimentin ; analysis ; genetics

OBJECTIVETo explore the clinicopathological, immunohistochemical, and molecular biologic characteristics of esophageal stromal tumors and smooth muscle tumors.

METHODSTwenty four cases of esophageal mesenchymal tumors were reclassified by a panel of antibodies such as CD117, CD34 etc. The sequence of 11 exon of c-kit gene were detected in some cases.

RESULTSThere were 3 cases of esophageal stromal tumors, 20 leiomyomas, and 1 leiomyosarcoma. The 3 esophageal stromal tumors occurred in 3 men aged 71, 56 and 60 years respectively. The tumors originated from muscularis propria with the size of 4 cm, 8 cm and 14 cm in diameter. Microscopically, the tumor cells were spindle and epithelioid shaped with slightly basophilic appearance, arranged in intersecting fascicles, diffusing and palisading patterns. Immunohistochemically, the tumors were positive for CD117 and CD34. The mutation of 11 exon of c-kit gene was detected in one case. In comparison, esophageal leiomyomas occurred in a younger population. The age ranged from 30 to 60 years (mean age 41.6 years), 12 male cases, 8 female cases. 15 cases of esophageal leiomyomas were intramural tumors with a diameter of 0.8 - 10.5 cm (mean 4.5 cm) originating from muscularis propria and 5 cases which were intraluminal polyps with a diameter of 0.2 - 1.0 cm originating from muscularis mucosae. Leiomyomas were strongly eosinophilic in appearance, diffuse positivity for alpha-SMA, MSA, and desmin, and no c-kit gene mutation. One male case of leiomyosarcoma had a diameter of 5 cm and originated from muscularis mucosae and displayed a sausage-shaped polyp.

CONCLUSIONSLeiomyoma is still the most common mesenchymal tumor of the esophagus, the stromal tumor can be similar to gastrointestinal stromal tumors. Typical esophageal leiomyosarcoma is very rare and has different clinicopathologic and molecular biologic features.

Actins ; analysis ; Adult ; Aged ; Antigens, CD34 ; analysis ; Base Sequence ; Desmin ; analysis ; Esophageal Neoplasms ; genetics ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Leiomyoma ; genetics ; metabolism ; pathology ; Leiomyosarcoma ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Muscle, Smooth ; metabolism ; pathology ; Mutation ; Proto-Oncogene Proteins c-kit ; analysis ; genetics ; Stromal Cells ; metabolism ; pathology

OBJECTIVETo study the clinicopathological and genetic features of desmoid-type fibromatosis, and to investigate the feasibility of detecting trisomy 8 in formalin fixed, paraffin embedded (FFPE) tissue by fluorescence in-situ hybridization (FISH).

METHODSA total of 96 cases were included in this study. All patients had clinical information. Histopathologic and immunohistochemical evaluations were available in 69 cases, and ultrastructural evaluation was done in 2 cases of desmoid-type fibromatosis. FFPE tissue sections were available in 20 tumors for the trisomy 8 detection by FISH.

RESULTSThere were 20 male and 76 female patients with ages ranging from 8 to 86 years (mean 35.3 years). Clinically, there were 44 extra-abdominal tumors, 28 abdominal wall tumors and 23 intra-abdominal lesions mostly involving the mesentery. Most cases presented with nodular or funicular masses with white firm cut surfaces, measuring 0.6 to 24.0 cm (mean 8.4 cm) in size. Histologically, desmoid-type fibromatoses showed longitudinal fascicles of spindle fibroblasts and myofibroblasts in a predominantly collagenous background. The tumor cells stained positive for vimentin, alpha-smooth muscle actin, desmin, and beta-catenin (47.8%, 33/69). Ultrastructurally, most tumor cells had features of fibroblasts, including rich endoplasmic reticulum and Golgi apparatus. Some tumor cells were myofibroblast-like cells exhibiting intercellular junctions, fibronexous junctions and stress fibers. Trisomy 8 was detected in 6 of 20 cases of desmoid-type fibromatosis including 5 of the 8 recurrent tumors but only one of the 12 primary tumors. The latter tumor also recurred three years later.

CONCLUSIONSDesmoid-type fibromatosis is an intermediate (locally aggressive) tumor that occurs predominantly in young females. The lesion consists of fibroblasts and myofibroblasts with the latter showing characteristic features including stress fibers and fibronexous junctions. Trisomy 8 can be detected in FFPE tissue by FISH, and its presence serves as a useful predictor of tumor recurrence and may define a subtype of desmoid-type fibromatosis with high recurrence rate.

Actins ; analysis ; Adult ; Aged ; Aged, 80 and over ; Child ; Chromosomes, Human, Pair 8 ; genetics ; Desmin ; analysis ; Feasibility Studies ; Female ; Fibromatosis, Abdominal ; genetics ; metabolism ; pathology ; Fibromatosis, Aggressive ; genetics ; metabolism ; pathology ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Male ; Mesentery ; Middle Aged ; Muscle, Smooth ; chemistry ; Neoplasm Recurrence, Local ; Peritoneal Neoplasms ; genetics ; metabolism ; pathology ; Trisomy ; Vimentin ; metabolism ; beta Catenin ; analysis