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R C Trembath

Publications and source records attributed to R C Trembath.

At least 19 recordsLinked to original sources
PubMed2006

A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort.

OBJECTIVE: To investigate the molecular genetic basis of cluster headache (CH), using a genome-wide scan and candidate gene strategy. METHODS: Northern European CH families and a case-control cohort of Danish, Swedish, and British origin (total n = 259 sporadic CH patients), including 267 control subjects matched for ancestry, participated in the study. A genome-wide genetic screen using approximately 400 microsatellite markers was performed for five informative Danish CH families. Additional markers were typed for those loci generating statistical evidence suggestive of linkage, together with genotypes for 111 individuals from further Danish and Italian kindreds. Sporadic CH patients and controls were investigated by association analysis for variation in the candidate gene, HCRTR2. Finally, complete HCRTR2 sequencing was undertaken for eight independent probands. RESULTS: Potential linkage was identified at four possible disease loci in Danish kindreds, yet no single chromosome location generated a lod or NPL score of recognized significance. No deleterious sequence variants of the HCRTR2 gene were detected by comparison to wild-type sequence. Association of the HCRTR2 gene was not replicated in this large dataset, even when the data were stratified into distinct populations. CONCLUSIONS: Cluster headache is a complex genetic disorder, with possible phenotypic and genetic heterogeneity compounding attempts at gene identification.

Adolescent↗
PubMed2006

Evidence of an association between desmoglein 3 haplotypes and pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV, OMIM 169610) is a severe blistering disorder of the skin and mucous membranes, caused by the production of autoantibodies directed against the epithelial adhesive protein desmoglein 3. Although an association between PV and HLA class II alleles has been established, the genetic factors predisposing to the disease remain poorly understood, the rarity of PV hampering the recruitment of substantial patient cohorts. OBJECTIVES: To investigate DSG3 as a candidate PV susceptibility gene. METHODS: We examined five DSG3 single nucleotide polymorphisms (rs8085532, rs3911655, rs3848485, rs3794925 and rs1466379) in two case-control datasets respectively originating from the U.K. (62 PV patients, 154 controls) and northern India (28 patients, 98 controls). RESULTS: In the U.K. sample, we observed a significant association between PV and the DSG3*TCCTC haplotype (Fisher's exact test P = 0.002). A related haplotype (DSG3*TCCCC) was associated with PV in the Indian dataset (P = 0.002). We also found that all British and Indian patients bearing DSG3 risk haplotypes carried at least one copy of a PV-associated HLA allele. CONCLUSIONS: These results suggest that genetic variation of DSG3 may be an additive risk factor predisposing to PV and warrant further investigations of this gene.

Case-Control Studies↗
PubMed2005

A dual-light reporter system to determine the efficiency of protein-protein interactions in mammalian cells.

Methods for determining protein-protein interactions in mammalian cells typically rely on single reporter functions and are susceptible to variations between samples particularly in regard to levels of transcription, processing and translation. A method has been developed for determining protein-protein interactions in mammalian cells, which bypasses these variables confounding single reporter assays. The approach utilizes two units of gene expression linked to reporter functions that are interposed by a deactivation-activation unit in such a way that the downstream expression unit is switched off. Hence upstream expression occurs regardless of protein-protein interaction, leading to the production of the upstream reporter. In the event of protein-protein interactions, the downstream expression unit is switched on leading to dual reporter read outs. Thus, the ratio of the two reporter activities provides a measure to determine the efficiency of protein-protein interactions. To access the system we screened a mutant of BMPR2 where the interaction between BMPR-II and LIMK is abrogated. BMPR-II is a type II receptor of the TGFbeta superfamily and plays a key role in the pathogenesis of familial pulmonary arterial hypertension. This system has potential for high-throughput screening of libraries (peptide, chemical, cDNA, etc.) to isolate agents that are capable of interfering with highly selective protein-protein interaction.

Bone Morphogenetic Protein Receptors, Type II↗
PubMed2005

Genomic duplication in Dyggve Melchior Clausen syndrome, a novel mutation mechanism in an autosomal recessive disorder.

BACKGROUND: Dyggve Melchior Clausen syndrome (DMC) is a severe autosomal recessive skeletal dysplasia associated with mental retardation. Direct sequencing of genomic DNA has identified causative mutations in the gene Dymeclin (chromosome 18q12-21), with the majority predicting the generation of a truncated protein product. OBJECTIVE: To carry out molecular genetic studies in three DMC kindreds. RESULTS: Two novel nonsense mutations and two complex genomic duplication events resulting in exon repetition were identified. CONCLUSIONS: Exon dosage assessment or mRNA analysis, in addition to direct genomic DNA sequencing, should be employed in the investigation of DMC affected individuals. Genomic duplication may be the causative mutation mechanism in other autosomal recessive disorders.

Family Health↗
PubMed2003

A Crohn's disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis.

A C-insertion polymorphism in the NOD2 gene (3020insC) on chromosome 16 is a rare mutation associated with Crohn's disease. Crohn's disease and psoriasis are more commonly observed together than expected by chance. Furthermore a susceptibility locus for psoriasis has been identified on chromosome 16q which overlaps the recently identified susceptibility locus for Crohn's disease. Thus, NOD2 may potentially be important as a candidate susceptibility gene for psoriasis. We tested this hypothesis by genotyping psoriasis patients for the C-insertion polymorphism using the Taqman ABI 7700 sequencing system. No statistically significant differences were observed between psoriasis vulgaris (n = 216), palmo-plantar pustular psoriasis (PPP) (n = 100), guttate psoriasis (n = 118) and the control group (n = 283). In both patient and control groups, no mutant homozygotes were observed and approximately 4% were heterozygotes. This particular insertion mutation in the NOD2 gene does not appear to contribute to the genetic susceptibility of psoriasis vulgaris, PPP or guttate psoriasis. However, other mutations exist in the NOD2 gene, which may potentially have a role in psoriasis susceptibility.

Adolescent↗
PubMed2003

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Activin Receptors, Type I↗
PubMed2003

A locus for asphyxiating thoracic dystrophy, ATD, maps to chromosome 15q13.

Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed a genome wide linkage search using autozygosity mapping in a cohort of four consanguineous families with ATD, three of which originate from Pakistan, and one from southern Italy. In these families, as well as in a fifth consanguineous family from France, we localised a novel ATD locus (ATD) to chromosome 15q13, with a maximum cumulative two point lod score at D15S1031 (Zmax=3.77 at theta=0.00). Five consanguineous families shared a 1.2 cM region of homozygosity between D15S165 and D15S1010. Investigation of a further four European kindreds, with no known parental consanguinity, showed evidence of marker homozygosity across a similar interval. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of two candidate genes, GREMLIN and FORMIN, did not show pathogenic mutations.

Asphyxia↗
PubMed2003

Neuro-otological findings in Pendred syndrome.

Pendred syndrome is an autosomal recessive inherited disorder characterized by profound hearing impairment and inappropriate iodine release by the thyroid on perchlorate challenge. Thirty-three cases comprising members of 13 families and eight isolated cases were studied, with detailed audiological and vestibular investigation and computerized tomography. A uniform, profound, symmetrical sensorineural hearing loss was identified in all cases. Approximately one-third of the group reported progressive hearing impairment, in childhood or adolescence, associated with head injury, infection, or delayed secondary hydrops. Ninety per cent of the cases scanned showed dilated vestibular aqueducts, and all cases with progression of the hearing impairment demonstrated this structural abnormality. Approximately one-third of the cases had normal vestibular function, but a further third demonstrated a unilateral peripheral deficit, while the remaining third showed bilateral vestibular hypofunction. There was no intra-familial concordance of vestibular findings, and no correlation between vestibular abnormality and presence or absence of a dilated vestibular aqueduct, with or without a Mondini malformation. In older children and adults, Pendred syndrome was associated with a profound, symmetrical, sensorineural auditory impairment, and a variety of vestibular abnormalities, which are not uniform within families, or correlated with structural labyrinthine deformities.

Adolescent↗
PubMed2002

Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2).

OBJECTIVE: To determine the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis. DESIGN AND METHODS: A large consanguineous Pakistani family containing six subjects with autosomal recessive complete achromatopsia was ascertained. After excluding linkage to the two known achromatopsia genes (CNGA3 and CNGB3), a genome wide linkage screen was undertaken. RESULTS: Significant linkage was detected to a 12 cM autozygous segment between markers D1S485 and D1S2881 on chromosome 1p13. Direct sequence analysis of the candidate gene GNAT2 located within this interval identified a frameshift mutation in exon 7 (c842_843insTCAG; M280fsX291) that segregated with the disease. CONCLUSIONS: The GNAT2 gene codes for cone alpha-transducin, the G protein that couples the cone pigments to cGMP-phosphodiesterase in phototransduction. Although cone alpha-transducin has a fundamental role in cone phototransduction, mutations in GNAT2 have not been described previously. Since mutations in the CNGA3 gene may cause a variety of retinal dystrophies (complete and incomplete achromatopsia and progressive cone dystrophy), GNAT2 mutations may also prove to be implicated in other forms of retinal dystrophy with cone dysfunction.

Amino Acid Sequence↗
PubMed2002

Genetics of pulmonary hypertension: from bench to bedside.

Primary pulmonary hypertension has been described as either sporadic or clustered in families. Familial primary pulmonary hypertension segregates as an autosomal dominant trait with markedly reduced disease gene penetrance. Defects within bone morphogenetic protein receptor type II gene, coding for a receptor member of the transforming growth factor-beta family, underlie familial primary pulmonary hypertension. Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. In addition, a proportion of so-called sporadic primary pulmonary hypertension turns out to have an inherited basis, as demonstrated by germline bone morphogenetic protein receptor type II gene mutations. Analysis of cases in association with hereditary haemorrhagic telangiectasia led to the demonstration that pulmonary arterial hypertension can involve activin-receptor-like kinase 1 mutations, a type I transforming growth factor-beta receptor. These findings emphasise the critical role of the transforming growth factor-beta signalling pathway in pulmonary arterial hypertension. While this achievement has generated extreme interest, the pathobiology of severe pulmonary arterial hypertension remains unclear and genomic approaches to pulmonary hypertension research may identify additional molecular determinants for this disorder. Finally, there is an urgent need to develop relevant guidelines for genetic counselling to assist patients, their relatives and pulmonary vascular specialists to utilise these recent observations.

Activin Receptors, Type I↗
PubMed2001

Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins.

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-beta superfamily members. METHODS AND RESULTS: For studies of (3)H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-beta(1) (10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated (3)H-thymidine incorporation, and TGF-beta(1) and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-beta(1) stimulated (3)H-thymidine incorporation (200%; P<0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription-polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-betaRI, Alk-1, ActRI, and BMPRIB) and type II (TGF-betaRII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with (125)I-TGF-beta(1) confirmed that the abnormal responses in PPH cells were not due to differences in TGF-beta receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-betaRII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates. CONCLUSIONS: We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-beta(1) and BMPs and that altered integration of TGF-beta superfamily growth signals may contribute to the pathogenesis of PPH.

Activin Receptors↗