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Results for “monogenic”

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At least 199 records · Page 11Linked to original sources
PubMed2006

Linkage of monogenic infantile hypertrophic pyloric stenosis to chromosome 16p12-p13 and evidence for genetic heterogeneity.

Infantile hypertrophic pyloric stenosis (IHPS) is the most common form of bowel obstruction in infancy. The disease affects males four times more often than females and is considered a paradigm for the sex-modified model of multifactorial inheritance. However, pedigrees consistent with autosomal dominant inheritance have also been documented. We analyzed a 3-generation family with IHPS including 10 affected individuals (5 males and 5 females) and mapped the underlying disease locus to chromosome 16p12-p13 (LOD score 3.23) by using a single-nucleotide polymorphism-based genomewide scan. The analysis of 10 additional multiplex pedigrees yielded negative or nonsignificant LOD scores, indicating the presence of locus heterogeneity. Sequence analysis of candidate genes from the chromosome 16 disease interval excluded the presence of pathogenic mutations in the GRIN2A and MYH11 genes.

Chromosome Mapping↗
PubMed2004

Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.

The clinical phenotype of heterozygous familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. It is inherited as an autosomal dominant disorder with homozygotes having a more severe phenotype than do heterozygotes. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified proprotein convertase subtilisin/kexin type 9 gene (PCSK9). To date, over 700 variants have been identified in the LDLR gene. With the exception of a small number of founder populations where one or two mutations predominate, most geographically based surveys of FH subjects show a large number of mutations segregating in a given population. Studies of the prevalence of FH would be improved by the use of a consistent and uniformly applied clinical definition. Because FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk is beneficial. Cascade testing of FH family members is cost effective and merits further research. For screening to be successful, public health and general practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.

Adult↗
PubMed2005

ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome.

Correct folding of nascent polypeptide chains within the ER is critical for function, assembly into multi-subunit complexes and trafficking through the exocytic pathway for secretory and cell surface proteins. This process is rather inefficient, and a substantial proportion of nascent polypeptides is rejected by an ER quality control system and targeted for degradation. In some cases, only a minor fraction of nascent chains is correctly folded, and the smallest alteration to polypeptide primary structure (i.e. point mutation) can result in the complete loss of function with inherent pathological consequences; cystic fibrosis and emphysema result from such mutations. We have taken a bioinformatic approach to parse a large database of known disease susceptibility genes for candidates whose disease-associated alleles are likely prone to misfolding in the ER. Surprisingly, we find that proteins with ER-targeting signals are over represented in this database when compared with all predicted proteins in the human genome (45 versus 30%). We selected a subgroup of proteins that were positive for both an ER-targeting signal and a membrane-anchoring domain and thereby identified several ER-associated degradation diseases candidates. To determine whether our analysis had identified new ER-degradation substrates, we established that ER retention is indeed the mechanism underlying Robinow syndrome (RRS), one of the identified candidates. Specifically, mutant alleles of ROR2 that are associated with RRS are retained within the ER, whereas wild-type and non-pathogenic alleles are exported to the plasma membrane. These data both uncover a major pathogenic factor for RRS and indicate that misfolding of secretory proteins is likely to significantly contribute to human disease and morbidity.

Abnormalities, Multiple↗
PubMed2006

Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes.

The generation of multiple transcripts by mRNA processing has the potential to moderate differences in gene expression both between tissues and at different stages of development. Where gene function is compromised by mutation, the presence of multiple isoforms may influence the resulting phenotype. Heterozygous mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HNF1A or TCF1 gene) result in early-onset diabetes as a result of pancreatic beta-cell dysfunction. We investigated the expression of the three alternatively processed isoforms of the HNF1A gene and their impact on the phenotype associated with mutations. Real-time PCR demonstrated variation in tissue expression of HNF1A isomers: HNF1A(A), with the lowest transactivation activity compared with the truncated isoforms HNF1A(B) and HNF1A(C), is the major isomer in liver (54%) and kidney (67%) but not in adult pancreas (24%) and islets (26%). However, in fetal pancreas HNF1A(A) is the major transcript (84%), which supports developmental regulation of isomer expression. We examined whether the isomers affected by the mutation altered the diabetes phenotype in 564 subjects with 123 mutations in HNF1A. Mutations that affected only isomer HNF1A(A) (exons 8-10) were diagnosed later (25.5 years) than mutations affecting all three isomers (exons 1-6) (18.0 years) (P=0.006). This first genotype/phenotype relationship described for patients with HNF1A mutations is explained by isomer structure and not by either mutation type or functional domain. We conclude that all three isomers may be critical for beta-cell function and could play a role in both the developing and mature beta cell.

Adolescent↗
PubMed2005

Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders.

BACKGROUND: Human embryonic stem (hES) cells are pluripotent cells usually derived from the inner cell mass (ICM) of blastocysts. Because of their ability to differentiate into all three embryonic germ layers, hES cells represent an important material for studying developmental biology and cell replacement therapy. hES cell lines derived from blastocysts diagnosed as carrying a genetic disorder after PGD represent in vitro disease models. METHODS: ICMs isolated by immunosurgery from human blastocysts donated for research after IVF cycles and after PGD were plated in serum-free medium (except VUB01) on mouse feeder layers. RESULTS: Five hES cell lines were isolated, two from IVF embryos and three from PGD embryos. All lines behave similarly in culture and present a normal karyotype. The lines express all the markers considered characteristic of undifferentiated hES cells and were proven to be pluripotent both in vitro and in vivo (ongoing for VUB05_HD). CONCLUSIONS: We report here on the derivation of two hES cell lines presumed to be genetically normal (VUB01 and VUB02) and three hES cell lines carrying mutations for myotonic dystrophy type 1 (VUB03_DM1), cystic fibrosis (VUB04_CF) and Huntington disease (VUB05_HD).

Biomarkers↗
PubMed1995

Monogenic Recessive Mutations Causing Both Late Floral Initiation and Excess Starch Accumulation in Arabidopsis.

A recessive Arabidopsis mutation, carbohydrate accumulation mutant1 (cam1), which maps to position 22.8 on chromosome 3, was identified by screening leaves of ethyl methanesulfonate-mutagenized M2 plants stained with iodine for altered starch content. Increased starch content in leaves of the cam1 mutant was observed at the onset of flowering. This mutant also had a delayed floral initiation phenotype with more rosette leaves than the parental line. In addition, activities of several enzymes associated with starch metabolism were altered in the cam1 mutant. The late-flowering mutant gigantea (gi) also manifested an elevated starch level in leaves. However, not all late-flowering mutants had increased leaf starch content. Double mutants cam1 adg1 (for ADP-glucose pyrophosphorylase), cam1 pgm (for phosphoglucomutase), and gi pgm had no observable starch in leaves but showed the late-flowering phenotype, demonstrating that the elevated starch content is not the cause of late floral initiation. The pleiotropic effects of cam1 and gi suggest that they may play regulatory roles in starch metabolism and floral initiation. These data suggest that starch accumulation and floral initiation may share a common regulatory pathway.

Journal Article↗
PubMed1983

A probable monogenic form of polyostotic fibrous dysplasia.

A 37 year-old female patient with polyostotic fibrous dysplasia (PFD) is described. She presented the typical "café au lait" spots and severe bone involvement including a maxillary osteosarcoma. The father, four sibs, two nephews, two paternal aunts and two paternal first cousins were clinically examined, and seven of them also radiologically evaluated. "Café au lait" spots were found in the father, three sibs, one nephew, one aunt and one first cousin. Although no definite PFD bone lesions, mild radiological abnormalities were found in the father, three sibs and one nephew. These findings were interpreted as the variable expression of a pleiotropic gene. The present observation and three previous familial cases of this entity strongly suggest the existence of a form of PFD determined by an autosomal dominant gene.

Adolescent↗
PubMed1999

Idiopathic epilepsies with a monogenic mode of inheritance.

Idiopathic epilepsies account for approximately 40% of all epileptic diseases. For a long time, it has been known that genetic factors play a major role in the etiology of these diseases. Although oligogenic or polygenic inheritance is suspected in most of the common syndromes, a few rare idiopathic epilepsies are single-gene disorders. They offer a chance to identify candidate genes that also may be involved in epilepsies with complex inheritance. In recent years, major progress has been made regarding the analysis of genetic factors in idiopathic epilepsy. For the first time, gene defects could be linked to two idiopathic epilepsies. Mutations in the CHRNA4 gene, which codes for the alpha4 subunit of the neuronal nicotinic acetylcholine receptor, lead to autosomal dominant nocturnal frontal lobe epilepsy, a rare idiopathic partial epilepsy syndrome. Two highly homologous voltage-gated potassium channels, KCNQ2 and KCNQ3, were found to be mutated in benign familial neonatal convulsions.

Australia↗
PubMed2004

Aetiology of colorectal cancer and relevance of monogenic inheritance.

BACKGROUND AND AIMS: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. PATIENTS AND METHODS: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. RESULTS: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. CONCLUSIONS: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.

Acquired Immunodeficiency Syndrome↗