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R C Trembath

Publications and source records attributed to R C Trembath.

At least 37 records · Page 2Linked to original sources
PubMed2001

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension.

Activin Receptors↗
PubMed2001

Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci.

We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p. These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21. The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity.

Child↗
PubMed2001

Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.

The pathogenesis of all forms of psoriasis remains obscure. Segregation analysis and twin studies together with ethnic differences in disease frequency all point to an underlying genetic susceptibility to psoriasis, which is both complex and likely to reflect the action of a number of genes. We performed a genome wide analysis using a total of 271 polymorphic autosomal markers on 284 sib relative pairs identified within 158 independent families. We detected evidence for linkage at 6p21 (PSORS1) with a non-parametric linkage score (NPL)=4.7, p=2 x 10(-6) and at chromosome 1p (NPL=3.6, p=1.9 x 10(-4)) in all families studied. Significant excess (p=0. 004) paternal allele sharing was detected for markers spanning the PSORS1 locus. A further three regions reached NPL scores of 2 or greater, including a region at chromosome 7 (NPL 2.1), for which linkage for a number of autoimmune disorders has been reported. Partitioning of the data set according to allele sharing at 6p21 (PSORS1) favoured linkage to chromosomes 2p (NPL 2.09) and 14q (NPL 2.0), both regions implicated in previous independent genome scans, and suggests evidence for epistasis between PSORS1 and genes at other genomic locations. This study has provided linkage evidence in favour of a novel susceptibility locus for psoriasis and provides evidence of the complex mechanisms underlying the genetic predisposition to this common skin disease.

Age of Onset↗
PubMed2000

BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.

Adolescent↗
PubMed2000

A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium.

Primary pulmonary hypertension (PPH), an often fatal disorder, is characterized by sustained elevation of pulmonary artery pressure of unknown cause. In its familial form (FPPH), the disorder segregates as an autosomal dominant and displays markedly reduced penetrance. A gene for FPPH was previously localized to a 25-cM interval on the long arm of chromosome 2 (2q31-q33). We now report a complete yeast artificial chromosome (YAC) and bacterial artificial chromosome (BAC)/P1 artificial chromosome contig (PAC), assembled by STS content mapping, across a newly identified minimum nonrecombinant interval containing the gene designated PPH1. The physical map has served to establish polymorphic marker order unequivocally, enabling the establishment of detailed haplotypes for the region. Together with the identification of novel recombination events in affected individuals from six newly ascertained kindreds, these data have allowed the significant reduction of the minimum PPH1 critical interval to a 4.8-cM region. The region, flanked by the polymorphic markers D2S115 (centromeric) and D2S1384 (telomeric), corresponds to a minimum physical distance of 5.8 Mb at 2q33. Numerous expressed sequence tags and known genes were placed on the YAC/BAC contig spanning the PPH1 gene critical region.

Bacteriophage P1↗
PubMed2000

Activating and inactivating mutations in the human GNAS1 gene.

GNAS1 on chromosome 20 is a complex locus, encoding multiple proteins, of which G(s)alpha, the alpha-subunit of the heterotrimeric stimulatory G protein G(s), is of particular interest clinically. Amino acid substitutions at two specific codons lead to constitutive activation of G(s)alpha. Such gain-of-function mutations are found in a variety of sporadic endocrine tumors and in McCune-Albright syndrome, a sporadic condition characterized by multiple endocrine abnormalities. Heterozygous loss of G(s)alpha function results in the dominantly inherited condition, Albright hereditary osteodystrophy (AHO). Here we present a review of published GNAS1 mutations and report 19 additional mutations, of which 15 are novel. A diverse range of inactivating mutations has been detected, scattered throughout the gene but showing some evidence of clustering. Only one, a recurring 4 bp deletion in exon 7, could be considered common among AHO patients. The parental origin of the mutation apparently determines whether or not the patient shows end-organ resistance to hormones such as parathyroid hormone. G(s)alpha is biallelically expressed in all tissues studied to date and thus there is no direct evidence that this transcript is imprinted. However, the recent identification of other imprinted transcripts encoded by GNAS1 and overlapping G(s)alpha, together with at least one imprinted antisense transcript, raises intriguing questions about how the primary effect of mutations in GNAS1 might be modulated.

Fibrous Dysplasia, Polyostotic↗
PubMed2000

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

Amino Acid Sequence↗
PubMed2000

Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension.

Primary pulmonary hypertension (PPH), characterized by obstruction of pre-capillary pulmonary arteries, leads to sustained elevation of pulmonary arterial pressure (mean >25 mm Hg at rest or >30 mm Hg during exercise). The aetiology is unknown, but the histological features reveal proliferation of endothelial and smooth muscle cells with vascular remodelling (Fig. 1). More than one affected relative has been identified in at least 6% of cases (familial PPH, MIM 178600). Familial PPH (FPPH) segregates as an autosomal dominant disorder with reduced penetrance and has been mapped to a locus designated PPH1 on 2q33, with no evidence of heterogeneity. We now show that FPPH is caused by mutations in BMPR2, encoding a TGF-beta type II receptor (BMPR-II). Members of the TGF-beta superfamily transduce signals by binding to heteromeric complexes of type I and II receptors, which activates serine/threonine kinases, leading to transcriptional regulation by phosphorylated Smads. By comparison with in vitro studies, identified defects of BMPR-II in FPPH are predicted to disrupt ligand binding, kinase activity and heteromeric dimer formation. Our data demonstrate the molecular basis of FPPH and underscore the importance in vivo of the TGF-beta signalling pathway in the maintenance of blood vessel integrity.

Amino Acid Sequence↗
PubMed2000

Primary pulmonary hypertension: the pressure rises for a gene.

Primary pulmonary hypertension (PPH) represents the end stage of a disruption of pulmonary vascular integrity, of unknown cause. Although PPH is associated with several systemic disorders, there have hitherto been few clues as to the aetiological factors responsible for the pathogenesis of this condition. As an example of the application of modern molecular genetics and positional cloning, this leader describes the range of studies currently under way, which aim to find the gene that underlies PPH, and summarises the implications of the identification of such a gene.

Chromosomes, Human, Pair 2↗
PubMed2000

Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family.

BACKGROUND: Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-beta) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder. METHODS: We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH. RESULTS: We found a total of 11 different heterozygous germline mutations of the BMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the BMPR2 gene in sporadic PPH. CONCLUSION: The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives.

Adolescent↗
PubMed2000

Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy.

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.

Adipose Tissue↗
PubMed1999

Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3.

Psoriasis is a common inflammatory skin condition caused by genetic and environmental factors. Recent genome-wide linkage analyses have identified a locus encoding susceptibility to psoriasis and placed this gene in the 12 cM interval between markers D6S426 and D6S276 on chromosome 6p21.3. This is a broad region and encompasses the human major histocompatibility complex. We have sought to localize the susceptibility gene more precisely by exploiting the linkage, haplotype, and linkage disequilibrium information available through genotyping 118 affected sib pairs, their parents and other affected family members. A total of 14 highly polymorphic markers were genotyped, combining anonymous loci with the class I genes HLA-B and -C distributed across a genetic interval of approximately 14 cM including the entire major histocompatibility complex. Through the application of higher density mapping within the major histocompatibility complex, we identified those regions most commonly shared identical by descent in patients with psoriasis. Using the transmission-disequilibrium test, we found significant evidence of linkage and allelic association across an interval defined by the markers tn62 (p = 1.0 x 10(-7)), HLA-B (p = 4.0 x 10(-7)), and HLA-C (p = 2.7 x 10(-9)), a region encompassed within a 285 kb genomic DNA fragment. Hence these studies contribute to the refinement of the localization of a major psoriasis susceptibility gene and place the critical region near to HLA-C.

Adolescent↗
PubMed1999

Molecular analysis of SALL1 mutations in Townes-Brocks syndrome.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Abnormalities, Multiple↗
PubMed1999

Familial cryptic translocation between chromosomes 2qter and 8qter: further delineation of the Albright hereditary osteodystrophy-like phenotype.

Recently five patients with an Albright hereditary osteodystrophy (AHO)-like phenotype were reported to have a subtelomeric deletion of the long arm of chromosome 2. These patients showed a striking resemblance to a number of patients from a large pedigree known to us for a long time. After molecular confirmation of a subtelomeric deletion in one patient, FISH analysis was used and a cryptic translocation between the long arms of chromosomes 2 and 8, t(2;8)(q37.3;q24.3), was detected. Remarkably, five proven and 10 probable cases with a 2qter deletion were found in the family, but none with an 8qter deletion. This was not explained by increased fetal loss. The major clinical characteristics of terminal 2q deletion are a short, stocky build, round face, sparse hair, deeply set eyes, bulbous nose, thin vermilion border, brachymetaphalangism, seizures, and developmental delay. A specific behavioural phenotype consisting of periods of hyperkinesia and aggression can develop with age. The overall phenotype is sufficiently characteristic to allow clinical recognition. The cytogenetic and molecular studies did not narrow down the common deleted region. Both testing of additional 2q markers and characterisation of other AHO-like patients with 2q37 microdeletions may help to define the candidate gene region.

Adolescent↗