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Biomedical subjects

Peter N Ray

Publications and source records attributed to Peter N Ray.

15 recordsLinked to original sources
PubMed2006

Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies.

Isolated hemihyperplasia (IH) refers to a distinct diagnosis involving asymmetric overgrowth of single or multiple organs or regions of the body and can result from various genomic changes including molecular alterations of 11p15; these are paternal uniparental disomy (UPD), and alterations of methylation at two imprinting centers at 11p15: IC1 (H19) and IC2 (KCNQ1OT1). As little information is available on the molecular basis of tumor development in IH, or on the frequency of tumors in children with different molecular subtypes of IH, molecular testing was undertaken on 51 patients with IH and revealed: 8 (16%) with UPD, 3 (6%) with hypomethylation at KCNQ1OT1, and 0 with hypermethylation at H19. Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma). The 50% tumor frequency in patients with IH and UPD was statistically significantly higher than the 15% tumor frequency in those with IH and no molecular alteration detected (Fisher's exact test P = 0.047, OR 5.67). This is the first demonstration that UPD at 11p15 in patients with IH confers a higher tumor risk than in patients with IH without this molecular change. Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development.

Abnormalities, Multiple↗
PubMed2006

Grandpa and I have dystrophinopathy?: approach to asymptomatic hyperCKemia.

This report describes three males from a single kinship, ages 7, 8, and 67 years with clinically asymptomatic dystrophinopathy. The index case was an 8-year-old male evaluated for asymptomatic but persistently elevated serum creatine kinase levels. Muscle biopsy demonstrated a mild myopathy, without necrotic fibers. Immunostaining for dystrophin revealed a slight reduction in sarcolemmal reactivity for the amino terminus of dystrophin. Dystrophin gene analysis revealed a deletion of exon 45 to exon 51. Genetic analysis identified two other affected males (age 7 years and 67 years), as well as four female carriers in the same family. The 7-year-old male had mildly increased creatine kinase levels with normal muscle strength. The 67-year-old grandfather had normal neuromuscular examination and serum creatine kinase levels. Asymptomatic dystrophinopathy in late adulthood is exceptionally rare, and highlights the importance of consideration of dystrophin mutation analysis in patients with hyperCKemia, even in the absence of muscle weakness.

Aged↗
PubMed2005

The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are associated with cystic fibrosis (CF)-related monosymptomatic conditions, including idiopathic pancreatitis. We evaluated prospectively enrolled patients who had idiopathic recurrent acute pancreatitis or idiopathic chronic pancreatitis, healthy controls, CF heterozygotes, and CF patients (pancreatic insufficient or sufficient) for evidence of CFTR gene mutations and abnormalities of ion transport by sweat chloride and nasal potential difference testing. DNA samples from anonymous blood donors were controls for genotyping. At least one CFTR mutation or variant was carried in 18 of 40 patients (45%) with idiopathic chronic pancreatitis and in 6 of 16 patients (38%) with idiopathic recurrent acute pancreatitis but in only 11 of the 50 controls (22%, P=0.005). Most identified mutations were rare and would not be identified in routine genetic screening. CFTR mutations were identified on both alleles in six patient (11%). Ion transport measurements in patients with pancreatitis showed a wide range of results, from the values in patients with classically diagnosed CF to those in the obligate heterozygotes and healthy controls. In general, ion channel measurements correlated with the number and severity of CFTR mutations. Twelve of 56 patients with pancreatitis (21%) fulfilled current clinical criteria for the diagnosis of CF, but CFTR genotyping alone confirmed the diagnosis in only two of these patients. We concluded that extensive genotyping and ion channel testing are useful to confirm or exclude the diagnosis of CF in the majority of patients with idiopathic pancreatitis.

Adult↗
PubMed2005

Analysis of the glucocerebrosidase gene in Parkinson's disease.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized clinically by a combination of motor symptoms. Identifying novel PD genetic risk factors is important for understanding its pathogenesis. A recent study suggested that up to 21% of subjects with PD may have mutations in the glucocerebrosidase (GBA) gene. We investigated the GBA gene for mutations in 88 PD cases and 122 normal controls and detected the presence of heterozygous GBA mutations in 5 PD cases and in 1 control. Sequencing of the entire open reading frame of the GBA gene in a subset of 25 cases with early-onset PD (<50 years of age) uncovered no additional mutations. Our results demonstrate a marginally significant association of GBA mutations with PD and suggest that variations in the GBA gene may constitute a rare susceptibility factor for PD (P = 0.048).

Adolescent↗
PubMed2004

Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay.

Canavan disease (CD) is an autosomal recessive progressive neurodegenerative disorder prevalent in the Ashkenazi Jewish (AJ) population. The carrier rate for the most common mutations that cause CD in the AJ population is often quoted as 1:37-1:40. This is not supported by our finding of only two diagnosed cases of CD in the last 20 years in the Toronto AJ population of 160,000 and an estimated birth rate of 1,500-2,000 per year. Therefore, we embarked on a prevalence cross-sectional screening study to determine the carrier rate of CD in this population. In order to perform low-cost, high-throughput population testing for CD using molecular techniques, we first developed a novel molecular assay using multiplex fluorescent allele specific polymerase chain reaction (PCR) to test for the three most common mutations causing CD in the AJ population (A854C, C693A, C914A) and a neutral polymorphism at the site of the C693A mutation. During testing it was noted that individuals who were carriers of the A854C mutation also had a T polymorphism at the site of the C693A mutation (Y231X). We confirmed that in all A854C carriers the 854C mutation was in disequilibrium with the 693T polymorphism, indicating a founder chromosome for the A854C mutation in the AJ population. Twenty-five carriers were found from 1,423 samples yielding a carrier rate of 1:57, differing from the widely quoted frequency of 1:40 and supporting our observed frequency of disease.

Alleles↗
PubMed2003

Screening of patients with craniosynostosis: molecular strategy.

Craniosynostosis is the premature fusion of calvarial bones leading to an abnormal head shape. The craniosynostosis syndromes are clinically heterogeneous with overlapping features, which make an accurate diagnosis difficult at times. Although the clarification of a genetic lesion does not have a direct impact on patient management in many cases, there is a significant benefit in providing accurate prenatal diagnosis. Genetic counsellors are also able to offer better risk estimates of recurrences to non-manifesting carriers and their extended family members and for affected patients of reproductive age. Advances in gene discovery have shown that craniosynostosis syndromes delineated on clinical bases, with the possible exception of Apert syndrome, are genetically heterogeneous, and mutations have been found in fibroblast growth factor receptors (FGFR) 1, 2, 3 and TWIST. We surveyed 99 craniosynostosis patients at the molecular level and found mutations in 50 of them. Six novel point mutations were identified: three in FGFR2 and three in TWIST. Two Saethre-Chotzen patients with TWIST microdeletions at 7p21 were also found. The other mutations identified have been previously reported. In studying these 99 patients, we developed a diagnostic strategy for craniosynostosis testing, where sequential analysis of recurrent mutations was followed by selective sequencing. This algorithm makes testing of craniosynostosis disorders more efficient and cost-effective.

Craniosynostoses↗
PubMed2003

Cloning and characterization of human CADPS and CADPS2, new members of the Ca2+-dependent activator for secretion protein family.

The recent identification of some of the components involved in regulated and constitutive exocytotic pathways has yielded important insights into the mechanisms of membrane trafficking and vesicle secretion. To understand precisely the molecular events taking place during vesicle exocytosis, we must identify all of the proteins implicated in these pathways. In this paper we describe the full-length cloning and characterization of human CADPS and CADPS2, two new homologs of the mouse Cadps protein involved in large dense-core vesicle (LDCV)-regulated exocytosis. We show that these two genes have disparate RNA expression patterns, with CADPS restricted to neural and endocrine tissues and CADPS2 expressed ubiquitously. We also identify a C2 domain, a known protein motif involved in calcium and phospholipid interactions, in both CADPS and CADPS2. We propose that CADPS functions as a calcium sensor in regulated exocytosis, whereas CADPS2 acts as a calcium sensor in constitutive vesicle trafficking and secretion. CADPS and CADPS2 were determined to span 475 kb and 561 kb on human chromosomes 3p21.1 and 7q31.3, respectively. The q31-q34 of human chromosome 7 has recently been identified to contain a putative susceptibility locus for autism (AUTS1). The function, expression profile, and location of CADPS2 make it a candidate gene for autism, and thus we conducted mutation screening for all 28 exons in 90 unrelated autistic individuals. We identified several nucleotide substitutions, including only one that would affect the amino acid sequence. No disease-specific variants were identified.

Amino Acid Sequence↗
PubMed2002

Identification of Dp71 isoforms in the platelet membrane cytoskeleton. Potential role in thrombin-mediated platelet adhesion.

Utrophin is a component of the platelet membrane cytoskeleton and participates in cytoskeletal reorganization (Earnest, J. P., Santos, G. F., Zuerbig, S., and Fox, J. E. B. (1995) J. Biol. Chem. 270, 27259-27265). Although platelets do not contain dystrophin, the identification of smaller C-terminal isoforms of dystrophin, including Dp71, which are expressed in a wide range of nonmuscle tissues and cell lines, has not been investigated. In this report, we have identified Dp71 protein variants of 55-60 kDa (designated Dp71Delta(110)) in the membrane cytoskeleton of human platelets. Both Dp71Delta(110) and utrophin sediment from lysed platelets along with the high speed detergent-insoluble pellet, which contains components of the membrane cytoskeleton. Like the membrane cytoskeletal proteins vinculin and spectrin, Dp71Delta(110) and utrophin redistributed from the high speed detergent-insoluble pellet to the integrin-rich low speed pellet of thrombin-stimulated platelets. Immunoelectron microscopy provided further evidence that Dp71Delta(110) was localized to the submembranous cytoskeleton. In addition to Dp71Delta(110), platelets contained several components of the dystrophin-associated protein complex, including beta-dystroglycan and syntrophin. To better understand the potential function of Dp71Delta(110), collagen adhesion assays were performed on platelets isolated from wild-type or Dp71-deficient (mdx(3cv)) mice. Adhesion to collagen in response to thrombin was significantly decreased in platelets isolated from mdx(3cv) mice, compared with wild-type platelets. Collectively, our results provide evidence that Dp71Delta(110) is a component of the platelet membrane cytoskeleton, is involved in cytoskeletal reorganization and/or signaling, and plays a role in thrombin-mediated platelet adhesion.

Animals↗
PubMed2002

Genetic analysis of patients with the Saethre-Chotzen phenotype.

Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by craniofacial and limb anomalies. Intragenic mutations of the TWIST gene within 7p21 have been identified as a cause of this disorder. There is phenotypic overlap with other craniosynostosis syndromes, and intragenic mutations in FGFR2 (fibroblast growth factor receptor 2) and FGFR3 (fibroblast growth factor receptor 3) have been demonstrated in the other conditions. Furthermore, complete gene deletions of TWIST have also been found in a significant proportion of patients with Saethre-Chotzen syndrome. We investigated 11 patients clinically identified as having the Saethre-Chotzen phenotype and 4 patients with craniosynostosis but without a clear diagnosis. Of the patients with the Saethre-Chotzen phenotype, four were found to carry the FGFR3 P250R mutation, three were found to be heterozygous for three different novel mutations in the coding region of TWIST, and two were found to have a deletion of one copy of the entire TWIST gene. Developmental delay was a distinguishing feature of the patients with deletions, compared to patients with intragenic mutations of TWIST, in agreement with the results of Johnson et al. [1998: Am J Hum Genet 63:1282-1293]. No mutations were found for the four patients with craniosynostosis without a clear diagnosis. Therefore, 9 of our 11 patients (82%) with the Saethre-Chotzen phenotype had detectable genetic changes in FGFR3 or TWIST. We propose that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybridization (FISH) for deletion detection of TWIST, is sufficient to detect mutations in > 80% of patients with the Saethre-Chotzen phenotype.

Acrocephalosyndactylia↗
PubMed2002

Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.

Pfeiffer syndrome is clinically and genetically heterogeneous. Three clinical subtypes have been delineated based on the severity of acrocephalysyndactyly and associated manifestations. Severe cases are usually sporadic and caused by a number of different mutations in exons IIIa and IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. Mild cases are either sporadic or familial and are caused by mutations in FGFR2 or FGFR1, respectively. We report on two individuals with different novel de novo mutations in FGFR2. The first is a 17-year-old male who has a severe phenotype, within the spectrum of subtype 1 including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. This patient was found to have a novel complex mutation at the 3' acceptor site of exon IIIc of FGFR2, denoted as C952-3 del10insACC. The other patient, a 2-year-old female, has a mild phenotype, typical of the classic subtype 1 including brachycephaly with coronal synostosis and hypertelorism. She was also found to have a mutation at the 3' acceptor site (the same splice site) of exon IIIc of FGFR2, a point mutation designated as 952-1G-->A. Speculation on the molecular mechanisms that cause severe and mild phenotypes is presented in relation to these two cases.

Acrocephalosyndactylia↗
PubMed2002

Duchenne muscular dystrophy: current knowledge, treatment, and future prospects.

The cloning of the dystrophin gene has led to major advances in the understanding of the molecular genetic basis of Duchenne, Becker, and other muscular dystrophies associated with mutations in genes encoding members of the dystrophin-associated glycoprotein complex. The recent introduction of pharmaceutical agents such as prednisone has shown great promise in delaying the progression of Duchenne muscular dystrophy but there remains a need to develop more long-term therapeutic interventions. Knowledge of the nature of the dystrophin gene and the glycoprotein complex has led many researchers to think that somatic gene replacement represents the most promising approach to treatment. The potential use of this strategy has been shown in the mdx mouse model of Duchenne muscular dystrophy, where germ line gene transfer of either a full-length or a smaller Becker-type dystrophin minigene prevents necrosis and restores normal muscle function.

Animals↗
PubMedDate not supplied

Providing information at the point of care: educational diagnostic reports from a genetic testing service provider.

Strategies to facilitate the provisioning of genetic health-care services by primary care physicians will improve access to these services for the average patient while making the most efficient use of limited human and financial resources within the health-care system. Genetic laboratories have become a major source of information and consultation for clinicians ordering genetic tests. This article describes the development and evaluation of a program to provide physician-directed information from a molecular testing facility to assist physicians in selecting and counseling patients and interpreting genetic test results. Semi-structured telephone interviews were used to gather physicians' opinions about the utility of the program and the way in which the information was used in their practice. Forty-three percent of those interviewed were unfamiliar with some of the information provided, with test methodology and sensitivity/specificity most often identified as novel information. Fifty-two percent of pediatric specialists were unfamiliar with some aspect of the information Sheet, despite being the highest consumers of testing services in this sample. Pediatricians and pediatric specialists also rated the initiative highest in terms of its usefulness in their practice, followed by genetic specialists. Overall, physicians confirmed the utility of the program as an educational tool for themselves, and for other non-patient educational activities in which they are involved.

Attitude of Health Personnel↗