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Biomedical subjects

M Gencik

Publications and source records attributed to M Gencik.

16 recordsLinked to original sources
PubMed2003

A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity.

Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene. Recent studies on the subcellular localization revealed that the TRIM37 (KIAA0898) protein is located in peroxisomes. Therefore, MUL has been classified as a new peroxisomal disorder. Up to now, four mutations have been reported, all of which lead to frameshifts and truncated proteins. In this study, mutation screening was performed for the coding region of the TRIM37 gene in a Turkish family by means of RT-PCR and direct cDNA sequencing. We have identified a novel mutation resulting in a frameshift cosegregating within the family. Finally, we report on the presence of novel splice variants observed in lymphoblastoid cells and muscle tissue of normal subjects and patients.

Base Sequence↗
PubMed2003

TNFA promoter polymorphisms and narcolepsy.

Narcolepsy is a debilitating sleep disorder that affects up to 0.05% of individuals in Caucasian populations. It is highly associated with the HLA-DR2 group antigen or the HLA-DRB1*1501-DQB1*0602 haplotype, respectively. However, the HLA association by itself cannot sufficiently explain the increased risk to family members, as HLA-DR2 is quite common in the general population and most people harboring the respective genotype do not develop any symptoms of narcolepsy. Situated in the HLA class II region, the TNFA gene is translated into the pro-inflammatory cytokine TNF-alpha. TNFA promoter polymorphisms have been linked to several inflammatory and autoimmune diseases. We analyzed three SNP of the TNFA promoter and one adjacent microsatellite in 103 patients and 96 controls. The T-allele of the C-857T polymorphism was strongly associated with narcolepsy in the subgroup of DRB1*15/16 (HLA-DR2 type) negative patients, but not in DRB1*15/16 positive patients. These results point towards an etiological influence of TNFA alleles in narcolepsy and support previous findings suggesting genetic heterogeneity and differences in pathophysiological characteristics of HLA-DR2 positive and negative narcolepsy.

Alleles↗
PubMed2003

Increased frequency of migraine in narcoleptic patients: a confirmatory study.

Previously we have reported an increased prevalence of migraine in narcoleptic patients. Because of the theoretical and clinical implications of this finding we recruited an independent new study sample of 100 patients with proven narcolepsy and conducted a structured 26-item interview based on the international diagnostic criteria for headache disorders, the Kiel Headache Questionnaire. Narcolepsy symptoms were measured by means of the Stanford Centre for Narcolepsy Sleep Inventory. Migraine prevalence was twofold to fourfold increased in the narcoleptic patients and amounted to 44.4% in women and 28.3% in men. The onset of narcolepsy symptoms was 12.3 +/- 11.4 years before the onset of migraine symptoms. The results might be regarded as indicative of a common pathophysiological pathway relevant to both of the two disorders.

Adult↗
PubMed2002

Chorea Huntington: a rare case with childhood onset.

Chorea Huntington (CH) is a dominantly inherited, neurodegenerative disease usually with adult onset. The course of CH is characterized by movement disturbances, psychiatric symptoms and it may lead to dementia. Typically death occurs after 10 to 20 years of CH duration. Invariably, the underlying mutation concerns an expansion of a polymorphic (CAG) n stretch in the huntingtin gene. Statistically, larger expansions lead to earlier onset of the disease. We report on a girl with a huntingtin allele of > 140 (CAG) n repeats. Unspecific neurological symptoms were noted at the age of 4.3 years followed by rapid disease progression with psychomotor deterioration.

Alleles↗
PubMed2001

ApoE polymorphisms in narcolepsy.

BACKGROUND: Narcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well. METHODS: To clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls. RESULTS: The frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups. CONCLUSION: Our results exclude the ApoE4 allele as a major risk factor for narcolepsy.

Journal Article↗
PubMed2001

A prepro-orexin gene polymorphism is associated with narcolepsy.

The orexin (hypocretin) neurotransmitter system was recently shown to be directly involved in the pathogenesis of narcolepsy in two animal models. Furthermore, decreased levels of orexin A in the CSF were shown in narcoleptic patients. To define any genetic contribution of orexin to the etiology of narcolepsy, the authors screened the entire prepro-orexin gene for mutations or polymorphisms in 133 patients suffering from narcolepsy. They report an association of a rare polymorphism in the prepro-orexin gene with narcolepsy in a cohort of 178 patients.

DNA Primers↗
PubMed2001

Isolated loss of gamma-sarcoglycan: diagnostic implications in autosomal recessive limb-girdle muscular dystrophies.

Mutations in the sarcoglycan (SG) genes cause a subset of limb-girdle muscular dystrophies (LGMD). We report a Spanish patient with progressive LGMD exhibiting an almost isolated loss of gamma-SG and a homozygous Delta521-T mutation in the gamma-SG gene. These results suggest that isolated loss of gamma-SG might remain undetected using only the alpha-SG antibody in routine muscle biopsy studies. Both alpha- and gamma-SG antibodies should be used in the diagnostic detection of patients with LGMD.

Adult↗
PubMed2001

Alpha-sarcoglycanopathy previously misdiagnosed as Duchenne muscular dystrophy: implications for current diagnostics and patient care.

Differential diagnosis of limb-girdle muscular dystrophy, including alpha-sarcoglycanopathy and Duchenne muscular dystrophy, is impossible to acheive on clinical grounds alone; therefore immunohistology, Western blotting and molecular genetic analysis are manadatory for a correct diagnosis. The patient's genotype with a hitherto unknown mutation (Tyr134STOP) in exon 5 adds to the growing spectrum of mutations in the alpha-sarcoglycan gene.

Adolescent↗
PubMed2001

Novel SNPs in the CD18 gene validate the association with MPO-ANCA+ vasculitis.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg-Strauss syndrome (CSS) are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Anti-myeloperoxidase (MPO)-ANCA are a typical feature of MP and CSS, while anti-proteinase 3 (PRTN3)-ANCA are highly specific for WG. Several reports indicate that ANCA may directly contribute to pathological processes, ie, through an increase of adhesivity between polymorphonuclear (PMN) and endothelial cells (EC). PMN interact and endothelium interact via the adhesion cascade (AC). CD18 is a key molecule of the AC, as CD18 defects abrogate the adhesion of PMN and cause leukocyte adhesion deficiency, an immunodeficient trait. We have screened the entire coding and regulatory regions of the CD18 gene. Ten single nucleotide polymorphisms (SNP) were identified, four of them showing significant associations with MPO-ANCA(+) vasculitis. One of these SNP's was localized in an alternate transcription initiation site. This polymorphism may influence CD18 gene expression, resulting in dose-dependent increase in adhesion and consecutively facilitated degranulation and respiratory burst. In this manner the pro-adherent genotype may predispose to MPO-ANCA(+) vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

The association of CD18 alleles with anti-myeloperoxidase subtypes of ANCA-associated systemic vasculitides.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg Strauss syndrome (CSS) are rare systemic autoimmune disorders. Common features are anti-neutrophil cytoplasmic antibodies (ANCA) in patient sera. Whereas WG patients show mainly anti-proteinase 3 ANCA, MP and CSS patients typically present anti-myeloperoxidase (MPO) ANCA. ANCA play an important role in the pathogenesis in the vessel wall by activating polymorphonuclear cells (PMN) and increased adhesivity between PMN and endothelial cells via adhesion molecules. Here we investigated major adhesion molecules as predisposition factors via common polymorphisms in or in the vicinity of the candidate genes ICAM-1, e-selectin, PLAUR, CD11b, and CD18. A restriction fragment-length polymorphism in exon 11 of the CD18 gene was associated with MPO-ANCA(+) systemic vasculitis. Our data indicate that a common variant of the CD18 gene confers increased risk for CSS and MP, supporting that genetic factors are involved in the etiology and pathogenesis of ANCA-associated systemic vasculitides.

Alleles↗
PubMed2000

Proteinase 3 gene polymorphisms and Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis (WG) is a rare systemic autoimmune disease characterized by small-vessel vasculitis leading to organ damage and the presence of antineutrophil cytoplasmic autoantibodies (ANCAs). ANCAs were shown to be involved in the pathogenesis of the disease by increasing adhesion of polymorphonuclear cells (PMNs) to endothelial cells and through activation of primed PMN. The main autoantigen of ANCA in WG is proteinase 3 (PR3), a neutrophil- and monocyte-derived neutral serine protease. The association of WG with individuals continuously expressing a high level of PR3 on the surface of PMNs suggests that PR3 variants or altered regulation of PR3 expression might be directly involved in the pathogenesis of the disease. METHODS: We screened the entire coding and promoter sequences of the PR3 gene for polymorphisms by means of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). Allelic, genotypic, and haplotype frequencies were compared between 79 WG patients and a cohort of 129 healthy controls. RESULTS: Seven single-nucleotide polymorphisms (SNPs), one amino acid change (Val119Ile), one 84 bp insertion/deletion, and a microsatellite were identified. An association with WG could be demonstrated for the A-564G polymorphism in the PR3 promoter affecting a putative transcription factor-binding site. CONCLUSIONS: This study excludes certain PR3 epitope variants as autoantigenic stimuli in WG, since the Val119Ile polymorphism showed no differences between patients and controls. Overexpression of PR3, however, might predispose the patient to the development of autoimmune ANCA-associated vasculitis.

Alleles↗
PubMed1999

Immunogenetic risk factors for anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA-DRB1*13 and HLA-DQB1*0603 individuals was observed in our cohort of ANCA-associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA-DRB1*04 individuals were over-represented in a subgroup of patients with WG in end-stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)alpha, IL-2, IL-5 receptor alpha (IL-5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFalpha as well as in the coding region of the FcgammaIIRA genes. Polymorphisms of the TNFalpha promotor (TNF-308) as well as in the FcgammaIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL-2 and IL-5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)-ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.

Adolescent↗
PubMed1993

Multistep transformation in low-grade lymphoproliferative diseases.

BACKGROUND: Carcinogenesis, the formation of solid tumors, is now widely accepted to represent a multistep process. Several genetic events, activation of proto-oncogenes and inactivation of tumor suppressor genes, are involved. DESIGN: Review of the literature for evidence that the concept of multistep transformation has relevance also for the formation of low-grade lymphoproliferative diseases. RESULTS AND CONCLUSION: The common translocations in low-grade lymphoid tumors are probably early events, predominantly involved in the activation of oncogenes, leading to growth stimulation or prolonged cell survival. As a result 'monoclonal lymphoproliferative disorders of undetermined significance (MLDUS)' occur, undetermined, because some translocations may not always led to tumor formation. For progression to full malignancy, additional genetic events are required besides sequential selection of variant subpopulations within the neoplastic clone. Recent data indicate that mutations and deletions of putative tumor suppressor genes, including the P53 and retinoblastoma genes, are also involved in the progression of lymphoproliferative disorders. A list of lymphoproliferative diseases stressing this concept of multistep transformation is presented in this article.

Animals↗