Interleukin-10 haplotypes in Celiac Disease in the Spanish populationSpringer Science and Business Media LLC - Tập 7 Số 1 - 2006
Concepción Núñez, Diana Alecsandru, Jezabel Varadé, Isabel Polanco, Carlos Maluenda, Miguel Fernández‐Arquero, Emilio G. de la Concha, Elena Urcelay, Alfonso Martínez
AbstractBackgroundCeliac disease (CD) is a chronic disorder characterized by a pathological inflammatory response after exposure to gluten in genetically susceptible individuals. The HLA complex accounts for less than half of the genetic component of the disease, and additional genes must be implicated. Interleukin-10 (IL-10) is an important regulator of mucosal immunity, and several reports have described alterations of IL-10 levels in celiac patients. TheIL-10gene is located on chromosome 1, and its promoter carries several single nucleotide polymorphisms (SNPs) and microsatellites which have been associated to production levels. Our aim was to study the role of those polymorphisms in susceptibility to CD in our population.
MethodsA case-control and a familial study were performed. Positions -1082, -819 and -592 of theIL-10promoter were typed by TaqMan and allele specific PCR. IL10R and IL10G microsatellites were amplified with labelled primers, and they were subsequently run on an automatic sequencer. In this study 446 patients and 573 controls were included, all of them white Spaniards. Extended haplotypes encompassing microsatellites and SNPs were obtained in families and estimated in controls by the Expectation-Maximization algorithm.
ResultsNo significant associations after Bonferroni correction were observed in the SNPs or any of the microsatellites. Stratification by HLA-DQ2 (DQA1*0501-DQB1*02) status did not alter the results. When extended haplotypes were analyzed, no differences were apparent either.
ConclusionTheIL-10polymorphisms studied are not associated with celiac disease. Our data suggest that the IL-10 alteration seen in patients may be more consequence than cause of the disease.
An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3Springer Science and Business Media LLC - Tập 13 - Trang 1-8 - 2012
Ahmed Bouhouche, Ali Benomar, Leila Errguig, Lamiae Lachhab, Naima Bouslam, Jehanne Aasfara, Sanaa Sefiani, Layachi Chabraoui, Elmostafa El Fahime, Abdeljalil El Quessar, Mohamed Jiddane, Mohamed Yahyaoui
Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.
A novel VPS13B mutation in Cohen syndrome: a case report and review of literatureSpringer Science and Business Media LLC - Tập 21 - Trang 1-6 - 2020
Sara Momtazmanesh, Elham Rayzan, Sepideh Shahkarami, Meino Rohlfs, Christoph Klein, Nima Rezaei
Cohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations. A 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies. We reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia.
The Siblings With Ischemic Stroke Study (SWISS) ProtocolSpringer Science and Business Media LLC - Tập 3 - Trang 1-12 - 2002
James F Meschia, Robert D Brown, Thomas G Brott, Felix E Chukwudelunzu, John Hardy, Stephen S Rich
Family history and twins studies suggest an inherited component to ischemic stroke risk. Candidate gene association studies have been performed but have limited capacity to identify novel risk factor genes. The Siblings With Ischemic Stroke Study (SWISS) aims to conduct a genome-wide scan in sibling pairs concordant or discordant for ischemic stroke to identify novel genetic risk factors through linkage analysis. Screening at multiple clinical centers identifies patients (probands) with radiographically confirmed ischemic stroke and a family history of at least 1 living full sibling with stroke. After giving informed consent, without violating privacy among other family members, the proband invites siblings concordant and discordant for stroke to participate. Siblings then contact the study coordinating center. The diagnosis of ischemic stroke in potentially concordant siblings is confirmed by systematic centralized review of medical records. The stroke-free status of potentially discordant siblings is confirmed by validated structured telephone interview. Blood samples for DNA analysis are taken from concordant sibling pairs and, if applicable, from 1 discordant sibling. Epstein-Barr virus-transformed lymphoblastoid cell lines are created, and a scan of the human genome is planned. Conducting adequately powered genomics studies of stroke in humans is challenging because of the heterogeneity of the stroke phenotype and the difficulty of obtaining DNA samples from clinically well-characterized members of a cohort of stroke pedigrees. The multicentered design of this study is intended to efficiently assemble a cohort of ischemic stroke pedigrees without invoking community consent or using cold-calling of pedigree members.
Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotypeSpringer Science and Business Media LLC - Tập 13 - Trang 1-9 - 2012
Bridget A Fernandez, Jane S Green, Ford Bursey, Brendan Barrett, Andrée MacMillan, Sarah McColl, Sara Fernandez, Proton Rahman, Krista Mahoney, Sergio L Pereira, Stephen W Scherer, Kym M Boycott, Michael O Woods
Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.
Ovarian metastases from ileum cancer in a patient with germline EPCAM gene deletion successfully treated with surgical resection and CAPOX chemotherapy: a case reportSpringer Science and Business Media LLC - Tập 21 - Trang 1-6 - 2020
Narushi Iwata, Ayumi Shikama, Wataru Takao, Yoshihiko Hosokawa, Hiroya Itagaki, Nobutaka Tasaka, Azusa Akiyama, Hiroyuki Ochi, Takeo Minaguchi, Miwa Arita, Emiko Noguchi, Toshikazu Moriwaki, Toyomi Satoh
Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery. A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months. We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.
Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility geneSpringer Science and Business Media LLC - Tập 8 - Trang 1-8 - 2007
Richard G Del Mastro, Laura Turenne, Heidi Giese, Tim P Keith, Paul Van Eerdewegh, Klaus JW May, Randall D Little
ADAM33 has been identified as an asthma-associated gene in an out-bred population. Genetic studies suggested that the functional role of this metalloprotease was in airway remodeling. However, the mechanistic roles of the disease-associated SNPs have yet to be elucidated especially in the context of the pathophysiology of asthma. One disease-associated SNP, BC+1, which resides in intron BC toward the 5' end of ADAM33, is highly associated with the disease. The region surrounding this genetic variant was cloned into a model system to determine if there is a regulatory element within this intron that influences transcription. The BC+1 protective allele did not impose any affect on the transcription of the reporter gene. However, the at-risk allele enforced such a repressive affect on the promoter that no protein product from the reporter gene was detected. These results indicated that there exists within intron BC a regulatory element that acts as a repressor for gene expression. Moreover, since SNP BC+1 is a common genetic variant, this region may interact with other undefined regulatory elements within ADAM33 to provide a rheostat effect, which modulates pre-mRNA processing. Thus, SNP BC+1 may have an important role in the modulation of ADAM33 gene expression. These data provide for the first time a functional role for a disease-associated SNP in ADAM33 and begin to shed light on the deregulation of this gene in the pathophysiology of asthma.
A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case reportSpringer Science and Business Media LLC - Tập 19 - Trang 1-6 - 2018
Elena Buena-Atienza, Fadi Nasser, Susanne Kohl, Bernd Wissinger
Blue Cone Monochromacy (BCM) is a rare congenital cone dysfunction disorder with X-linked recessive mode of inheritance. BCM is caused by mutations at the OPN1LW/MW cone opsin gene cluster including deletions of the locus control region (LCR) and/or parts of the gene cluster. We aimed at investigating the clinical presentation, genetic cause and inheritance underlying a sporadic case of BCM. We report a 24-year-old male presenting with congenital photophobia, nystagmus and colour vision abnormalities. There was no history of retinal dystrophy in the family. Clinical diagnosis of BCM was supported by genetic investigations of the patient and his family members. Molecular genetic analysis of the OPN1LW/OPN1MW gene cluster revealed a novel deletion of about 73 kb in the patient encompassing the LCR. The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather. The present report provides the clinical findings and the genetic basis underlying a sporadic BCM case which is caused by a de novo deletion within the OPN1LW/MW gene cluster originating from the mother’s germline due to Alu-repeat mediated recombination. This is the first report of a de novo deletion resulting in BCM, highlighting the importance to consider BCM and perform genetic testing for this condition in male patients with cone dysfunction also in the absence of a positive family history.
Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMISpringer Science and Business Media LLC - Tập 10 Số 1 - 2009
Ineta Kalniņa, Ivo Kāpa, Valdis Pīrāgs, Vita Ignatoviča, Helgi B. Schiöth, Jānis Kloviņš
Abstract
Background
The agouti related protein (AGRP) is an endogenous antagonist of the melanocortin 4 receptor and is one of the most potent orexigenic factors. The aim of the present study was to assess the genetic variability of AGRP gene and investigate whether the previously reported SNP rs5030980 and the rs11575892, a SNP that so far has not been studied with respect to obesity is associated with increased body mass index (BMI).
Methods
We determined the complete sequence of the AGRP gene and upstream promoter region in 95 patients with severe obesity (BMI > 35 kg/m2). Three polymorphisms were identified: silent mutation c.123G>A (rs34123523) in the second exon, non-synonymous mutation c.199G>A (rs5030980) and c.131-42C>T (rs11575892) located in the second intron. We further screened rs11575892 in a selected group of 1135 and rs5030980 in group of 789 participants from the Genome Database of Latvian Population and Latvian State Research Program Database.
Results
The CT heterozygotes of rs11575892 had significantly higher mean BMI value (p = 0.027). After adjustment for age, gender and other significant non-genetic factors (presence of diseases), the BMI levels remained significantly higher in carriers of the rs11575892 T allele (p = 0.001). The adjusted mean BMI value of CC genotype was 27.92 ± 1.01 kg/m2 (mean, SE) as compared to 30.97 ± 1.03 kg/m2 for the CT genotype. No association was found between rs5030980 and BMI.
Conclusion
This study presents an association of rare allele of AGRP polymorphism in heterozygous state with increased BMI. The possible functional effects of this polymorphism are unclear but may relate to splicing defects.
SNP55, a new functional polymorphism of MDM2-P2 promoter, contributes to allele-specific expression of MDM2 in endometrial cancersSpringer Science and Business Media LLC - - 2015
Kyoko Okamoto, Ryosuke Tsunematsu, Tomoko Tahira, Kenzo Sonoda, Kazuo Asanoma, Hiroshi Yagi, Tomoko Yoneda, Kenshi Hayashi, Norio Wake, Kiyoko Kato
