1/103. The 1396del A mutation and a missense mutation or a rare polymorphism of the WRN gene detected in a French Werner family with a severe phenotype and a case of an unusual vulvar cancer. Mutations in brief no. 136. Online. The Werner's syndrome (WS) is a rare recessive disease characterized by an early onset of geriatric disorders. The Werner's syndrome gene (WRN) recently cloned, encodes for an helicase and therefore plays a role in DNA metabolism and dna repair. Here, we report the study of a French family with two affected members and numerous cancers. Using the protein truncation test and sequencing, we identified a homozygous mutation in the WRN gene. This mutation generates a frame shift leading to a very short 391 amino acids truncated protein without the helicase motif. A particularly severe phenotype of the affected patient was associated with an unusual vulvar cancer traditionaly observed in elderly patients and therefore likely to be related to the Werner's syndrome. An additional substitution of G for A at nucleotidic position 1392 was also described. We suggest that a relation between genotype and phenotype could exist in the studied family. ( info) |
2/103. A case of Werner's syndrome associated with osteosarcoma. We described a case of Werner's syndrome associated with osteosarcoma. A 37-year-old Japanese man was diagnosed as having Werner's syndrome by the presence of juvenile cataracts, skin sclerosis and hyperpigmentation of the feet, high-pitched voice, characteristic bird-like appearance of the face with beak-shaped nose, thinning of the entire skin and hyperkeratoses on soles, hyperlipemia, hyperuricemia, diabetes melitus, and the mutated responsible gene (WRN). He had a 3-month history of a tumor on his left forearm. Histologically, the tumor included four histological patterns; a malignant fibrous histiocytoma-like, a desmoid-like, a dermatofibrosarcoma protuberans-like, and a chondrosarcoma-like pattern. Tumoral osteoid formation was also found in the tumor. Therefore, the tumor was diagnosed as osteosarcoma. ( info) |
| The purpose of this study was to examine the molecular mechanism responsible for the defective insulin-stimulated glucose transport in cultured fibroblasts from a patient (VH) with clinical features of werner syndrome and severe insulin resistance. Thus, in cells derived from VH, the subcellular distribution, structure, functional activity, as well as plasma membrane insertion of GLUT1 glucose transporters were analyzed. Furthermore, the insulin signal transduction pathway leading to activation of phosphatidylinositol (PI) 3-kinase as well as components of GLUT1-containing membrane vesicles were characterized. In fibroblasts derived from VH, GLUT1 glucose transporters were overexpressed by 8-fold in plasma membranes (PM) and by 5-fold in high density microsomes, respectively. Exofacial photolabeling revealed that only 14% of the overexpressed PM-GLUT1 transporters were properly inserted into the plasma membrane. The complementary DNA structure of the patient's insulin receptor and the GLUT1 glucose transporter, the intrinsic activity of plasma membrane glucose transporters, the tyrosine phosphorylation, as well as the protein expression of insulin receptor substrate-1/2 and p85 alpha/beta- and p110 alpha/beta-subunits of PI 3-kinase were normal. However, insulin-stimulated association of the p85 subunit of PI 3-kinase was defective in fibroblasts derived from VH compared to those from controls, and this defect was associated with a reduced IRS-1-dependent activation of PI 3-kinase by 50.2% and 63.6% after incubation for 5 and 10 min with 100 nmol/L insulin, respectively. Furthermore, immunodetection of small GTP-binding Rab proteins in subcellular membrane fractions indicated a decreased expression of Rab4 in total cellular homogenates as well as in high density microsomes by 70% and 58%, respectively. After preparation of GLUT1-containing vesicles, Rab4 was not detected to be a component of these vesicles. Analysis of the PI 3-kinase in GLUT1-containing membrane vesicles revealed insulin-dependent targeting of the p85 subunit to the vesicles immunoadsorbed from VH and control fibroblasts. Importantly, the association of the p85 subunit as well as the p85-immunoprecipitable PI 3-kinase activity were markedly reduced in GLUT1-vesicles derived from the patient. In conclusion, impaired PI 3-kinase activity in GLUT1-containing membrane vesicles derived from fibroblasts of VH is associated with a defective docking and/or fusion process of glucose transporters with the plasma membrane and thus might contribute to the molecular defect causing insulin resistance in this patient. ( info) |
4/103. Acrogeria of the Gottron type in a mother and son. We report a familial case of acrogeria in a mother and son, with characteristic cutaneous involvement and no clinical signs of vascular ehlers-danlos syndrome (former EDS type IV) in spite of some tendency to bruising. The biochemical and molecular studies did not disclose any abnormality of collagen type iii, which favours the diagnosis of acrogeria. It appears that recognition of acrogeria as an entity is of clinical significance since these cases are not associated with systemic involvement, and specifically with rupture of vessels and internal organs, occasionnally occurring in EDS. ( info) |
| The patient was a 39-year-old Japanese male with a body height of 160 cm and weight of 48 kg who was diagnosed as werner syndrome of homozygote for mutation 4. His plasma total cholesterol (TC), triglycerides (TGs), high density lipoprotein-cholesterol (HDL-C) and apolipoprotein a-i (apo A-I) levels were 7.2, 2.1, 1 mmol/l and 128 mg/dl, respectively. During the clinical course of treatment of this patient, his plasma levels of HDL-C and apo A-I declined drastically to levels of as low as 0.2 mmol/l and 10 mg/dl, respectively, with concurrent reciprocal increase in plasma TG levels. plasma HDL-C, apo A-I and TG levels gradually returned to original values. lipoprotein lipase activity and mass in post-heparin plasma were markedly low when the apo A-I and HDL-C levels decreased to 10 mg/dl and 0.21 mmol/l, respectively, and these values improved when the apo A-I and HDL-C levels returned to more normal values of 106 mg/dl and 0.94 mmol/l, respectively. The result of direct sequence of the exon 3 and 4, and the promoter region of the apo A-I gene of the patient revealed no single nucleotide changes. These results suggest that in the present patient, impaired hydrolysis of TGs in TG-rich lipoproteins, is due at least in part to a decreased LPL enzyme level, reduced the formation of nascent HDL, resulting in unusually low plasma levels of HDL-C and apo A-I. ( info) |
6/103. Severe heart valve calcification in a young patient with werner syndrome. werner syndrome is a rare autosomal recessive disorder characterized by the appearance of premature aging. We report on severe aortic and mitral valve calcification in an 18-year-old girl, necessitating double valve replacement. These special cardiovascular findings are discussed with regard to diagnosis and treatment. ( info) |
7/103. Nuclear structure in normal and bloom syndrome cells. bloom syndrome (BS) is a rare cancer-predisposing disorder in which the cells of affected persons have a high frequency of somatic mutation and genomic instability. BLM, the protein altered in BS, is a RecQ DNA helicase. This report shows that BLM is found in the nucleus of normal human cells in the nuclear domain 10 or promyelocytic leukemia nuclear bodies. These structures are punctate depots of proteins disrupted upon viral infection and in certain human malignancies. BLM is found primarily in nuclear domain 10 except during s phase when it colocalizes with the werner syndrome gene product, WRN, in the nucleolus. BLM colocalizes with a select subset of telomeres in normal cells and with large telomeric clusters seen in simian virus 40-transformed normal fibroblasts. During s phase, BS cells expel micronuclei containing sites of DNA synthesis. BLM is likely to be part of a DNA surveillance mechanism operating during s phase. ( info) |
8/103. Hoarse voice resulting from premature ageing in Werner's syndrome. Werner's syndrome is characterized by clinical signs of premature ageing. A 42-year-old man presented with three-year history of hoarseness. Also noted were skin atrophy of the face and hands, ulcerations around the ankles, and a history of cataracts. A clinical diagnosis of Werner's syndrome was made. laryngoscopy revealed bowed vocal folds resulting in a spindle-shaped defect with glottal incompetence during phonation. Examination also revealed decreased maximum phonation time and vocal fatigue. At surgery, atrophy of the vocalis muscle was noted. Furthermore, degeneration of muscle fibres was noted in the temporalis muscle. The atrophic changes in the vocal folds that occur with ageing and result in an increased fundamental frequency were seen in this patient. The characteristic hoarseness of Werner's syndrome appears to be the result of premature ageing of the vocal-folds. ( info) |
9/103. Evaluation of insulin response in glucose tolerance test in a patient with Werner's syndrome: a 16-year follow-up study. To clarify the effect of Werner's syndrome (WS) on beta-islet cell function, the oral glucose tolerance test (OGTT) was repeatedly performed over a period of 16 years in one patient with WS. The data obtained on insulin secretion were assessed in this study. The patient was a 50-yr-old woman of consanguineous parentage. She presented with gray hair, cataracts, a beak-shaped nose and high-pitched voice. She was diagnosed as WS on the basis of her characteristic appearance. OGTT was performed 14 times during 9 admissions to our hospital. After ingestion of glucose, plasma glucose (PG) levels and immuno-reactive insulin (IRI) at 0, 30, 60, 90, 120 and 180 min were determined. PG levels during OGTT gradually increased during dietary therapy and, at the age of 48, insulin treatment was started [PG level at 120 min during OGTT at 46 yr (before treatment) was 1.5 times that at 34 yr]. Insulin secretion had also gradually decreased during the follow-up period (sum of IRI at 34 yr during OGTT post-treatment; 550.8 IU/ml, sum of IRI at 50 yr during OGTT post-treatment; 244.5 IU/ml). However, the insulinogenic indices were maintained at almost the same level value. Our results indicate that insufficient insulin secretion, which could not overcome insulin resistance, might play a crucial role in the pathophysiology and progression of diabetes in WS along with insulin resistance due to a post-receptor defect. ( info) |
10/103. Revascularization of femoropopliteal artery occlusion in Werner's syndrome. Report of a case and review of surgical literature in cardiovascular lesions. A patient with Werner's syndrome suffering from a chronic ulcer on the right ankle joint underwent femoropopliteal bypass and patch angioplasty combined with endarterectomy of the distal popliteal artery. Postoperative angiography showed satisfactory graft patency and distal run-off, and the ulcer improved. Femoropopliteal occlusive disease in Werner's syndrome tends to have poor run-off and the internal diameter of the popliteal artery with diffuse arteriosclerotic lesion is often too small to facilitate distal anastomosis. Therefore, a conventional bypass procedure is not always effective and an aggressive attitude is essential to obtain sufficient ankle blood pressure and improve the leg ulcer in Werner' syndrome. ( info) |