Davut Gül

A very frequent mutation and remarkable association of R761H with M694V mutations in Turkish familial Mediterranean fever patients

Familial Mediterranean fever (FMF) is an autosomal-recessive disease. It is characterized by recurring fever, abdominal pain, and serositis. The Mediterranean fever (MEFV) gene is localized on 16p13.3 and more than 35 mutations have been described to date. There are some differences in the gene mutations of FMF in the various ethnic groups. The aim of this study is to determine the frequency of the mutations which has been reported comparatively rare, to define the most effective mutation set, and to select the most suitable DNA analysis system for Turkish FMF patients. Mutations in 330 Turkish FMF patients with typical phenotypes from various regions of Turkey were evaluated for the research purposes. These patients were analyzed for six MEFV gene mutations by the NanoChip® Molecular Genetics Workstation. The most frequent mutation was M694V, identified in 50.00% of the alleles examined; M680I followed with 14.10% and V726A—9.70%. Consequently, we determined that R761H (n = 23; 3.48%) was the most frequent rare mutations in Turkish FMF patients. Frequency of the rare mutations were R761H (3.48%), E148Q (1.36%), and M694I (1.21%). All of these mutations were in the compound heterozygote state. Our study showed that R761H mutations were higher than it has been reported in literature until now and were mainly associated with M694V. We suggest that mutation R761H should be included in the mutation scanning analysis researches or considered if the patient has M694V/? mutation especially in Turkish FMF patients. Larger serial studies need to be done to investigate the rate and coexistence of these mutations.

Study of Autoimmunity in Klinefelter's Syndrome and Idiopathic Hypogonadotropic Hypogonadism

Sex hormones play an important role in determining the progression and severity of autoimmune diseases, but the in vivo mechanisms underlying this relation are poorly understood. The main objective of current study has been to compare the changes in neuroendocrine immune features and autoantibody profile in male patients with hypogonadotropic and hypergonadotropic hypogonadism, and to determine the relationships between sex hormones and immunologic parameters. Thirty-seven male patients with Klinefelters syndrome and 35 men with idiopathic hypogonadotropic hypogonadism who had no history of previous hormonal therapy and 30 healthy men were recruited in the study. Serum autoantibody profile, sex hormones, and immunologic parameters were studied. In conclusion, our findings suggest that both humoral and cellular immunity is enhanced in male hypogonadism. Klinefelters syndrome patients also had increased frequency of antiextractable nuclear antibodies and anticardiolipin antibodies positivity compared to idiopathic hypogonadotropic hypogonadism patients. It is possible that testosterone deficiency and increased levels of estradiol are primary responsible factors for this enhanced autoantibody production in Klinefelters syndrome patients.

Adipose tissue 11-beta-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-Phosphate Dehydrogenase gene expressions are increased in patients with type 2 diabetes mellitus

AIMS We have determined 11-beta-Hydroxysteroid Dehydrogenase Type 1 (HSD11B1) and Hexose-6-Phosphate Dehydrogenase (H6PD) mRNA expression levels in adipose tissues from patients with type 2 diabetes mellitus. METHODS Six non-diabetic and seven diabetic male patients who undergo elective abdominal surgery were included in the study and visceral and subcutaneous adipose tissue samples were obtained. Fresh preadipocyte cultures were administered to low and high glucose medium (11M and 25M) in vitro for 24h and mRNA extractions were performed. HSD11B1 and H6PD gene mRNA expression levels were determined by real-time PCR and compared. Glyceraldehyde-3-phosphate Dehydrogenase (G3PD) mRNA level is used as housekeeping gene expression. RESULTS HSD11B1 mRNA levels were significantly higher in patient with T2DM than controls in both visceral and subcutaneous adipose tissues (3.35+/-0.7 vs. 0.37+/-0.1; P=0.01 and 2.07+/-0.8 vs. 0.11+/-0.05; P=0.01, respectively). H6PD mRNA levels were also significantly higher in patient with T2DM than controls in both visceral and subcutaneous adipose tissues (3.95+/-1.2 vs. 1.95+/-0.8; P=0.050 and 2.23+/-1.1 vs. 0.46+/-0.1; P=0.043, respectively). CONCLUSIONS Failure to down-regulate HSD11B1 activity in patients with type 2 diabetes may contribute to the pathogenesis of T2DM. Subcutaneous and visceral adipose tissues similarly exhibit the same variation in patients with type 2 diabetes mellitus.

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

BackgroundEllis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.MethodsBecause of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations.ResultsWe identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals.ConclusionWe conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.

Adams-Oliver syndrome: further evidence for autosomal recessive inheritance.

We report a 7-year-old girl with Adams-Oliver syndrome who presented with extremely rare central nervous system anomalies including microcephaly, epilepsy, mental retardation and intracranial calcifications in addition to the classical scalp and limb defects.

Unusual features in a patient with neurofibromatosis type 1: Multiple subcutaneous lipomas, a juvenile polyp in ascending colon, congenital intrahepatic portosystemic venous shunt, and horseshoe kidney

We report a case that draws attention to a hitherto undescribed association of neurofibromatosis type 1 (NF1) with juvenile polyp, congenital intrahepatic portosystemic venous shunt, multiple subcutaneous lipomas, and horseshoe kidney. Our patient has fulfilled the National Institutes of Health consensus conference criteria for NF1 by having neurofibromas, axillary freckling, Lisch nodules, and café‐au‐lait spots. There is no family history of NF1 and his 7‐year‐old son has no stigmata of NF1. On the other hand, the patients family had a presumably dominant inheritance of horseshoe kidney: the father, proband, sister, and son of the other sister had a horseshoe kidney. The patient was investigated for mutations in the NF1 gene and PTEN, but no germline mutations were detected. The differential diagnosis for such a collection of hamartomatous, cutaneous, and vascular disorders includes the Proteus, Bannayan–Riley–Ruvalcaba, and Cowden syndromes. None of these diagnoses was convincingly confirmed in this patient.

Woodhouse and Sakati syndrome (MIM 241080): report of a new patient.

A 32-year-old male with Woodhouse Sakati syndrome (MIM 241080) is described. Two of the probands brothers also have diabetes mellitus and similar facial features, however they are not dysarthric. An affected older brother died of an unknown cause at age 30. This confirms autosomal recessive inheritance.

The phenotype-genotype correlations of FMF patients: a single center study.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent self-limited episodes of fever and serosal inflammation accompanied by acute-phase response. The cloned FMF gene (MEFV) with 30-point mutations maps to chromosome 16p and encodes a 781-amino acid protein called pyrin or marenostrin. The common mutations are M694V (Jews, Turks, and Armenians), M680I (Armenian), M694I (Arabs), E148Q (Europeans, Turks) and V726A located on exon 2 and mainly 10 [1]. Fever (96%), peritonitis (91%), pleurisy (57%), arthritis/arthralgia (45%), erisipelas-like erythema (13%), and amyloidosis (2%) are the cardinal signs of the disease [2]. With an insight to clarify the pathogenesis of FMF, we retrospectively studied the mutation–clinical correlations. Materials and methods

A large deletion (1.5 Mb) encompassing the neurofibromatosis type 1 (NF1) gene in a patient with sporadic NF1 associated with dysmorphism, mental retardation, and unusual ocular and skeletal features.

&NA; A 20 year old male patient with sporadic neurofibromatosis type 1 (NF1) is described with a large deletion (1.5 Mb) involving the NF1 gene, dysmorphism, mental retardation, and unusual ocular and skeletal features. Several NF1 patients with a large NF1 deletion and associated dysmorphism, and a large number of neurofibromas for their age have been described. This study indicates that such large deletions can also involve flanking loci which affect ocular and skeletal development. Clin Dysmorphol 12:199‐201

Caudothalamic groove cysts in Zellweger syndrome.

The cerebro-hepato-renal syndrome of Zellweger is the most severe peroxisome biogenesis disorder. Zellweger syndrome is caused by a disturbance in the peroxisomal protein import machinery and leads to multiple organ defects and death usually within the first year of life. Here we report a 3-month-old girl with Zellweger syndrome who was found to have cysts in the caudothalamic groove on cranial magnetic resonance imaging.