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P I Patel

Publications and source records attributed to P I Patel.

At least 19 recordsLinked to original sources
PubMed1997

Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype.

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5 revealed a 1.1-kb intronic fragment followed by a related ORF of 2.5 kb that encodes the near full-length ORF for hTOP3, the first mammalian topoisomerase III to be identified. Endogenous expression of hTOP3 was found in all human tissues tested. Both pCAT4.5 and an antisense hTOP3 construct were able to inhibit spontaneous and radiation-induced apoptosis in A-T fibroblasts, whereas overexpression of a full-length hTOP3 cDNA did not. We postulate that topoisomerase III may be deregulated in A-T cells and that CAT4.5 complements the A-T phenotype via a dominant-negative mechanism. Furthermore, functional correction of hyper-recombination in A-T cells by CAT4.5 supports the hypothesis that the hTOP3 topoisomerase is involved in the control of genomic stability, perhaps in concert with the Bloom or Werner syndrome DNA helicases.

Apoptosis↗
PubMed1997

Familial essential tremor in 4 kindreds. Prospects for genetic mapping.

OBJECTIVES: To describe 4 large families with essential tremor (ET) to draw attention to the marked clinical heterogeneity of ET. To use computer simulation analysis to provide information about the power of the family material for future linkage studies. SUBJECTS: We examined a total of 251 members from 4 kindreds with ET. The mean (+/-SD) age at onset of ET varied among the 4 kindreds between 19.0 +/- 11.4 years and 45.6 +/- 7.4 years. Three of the kindreds had a total of 41 members with the combination of ET and dystonia, typically manifested as torticollis or dystonic writers' cramp. In 1 of the kindreds, ET seemed to be associated with malignant hyperthermia. One kindred represented "pure" ET without any associated disorders. METHODS: In addition to detailed clinical assessments, we conducted computer simulations on the families' pedigrees using a model that presumed an autosomal dominant inheritance pattern with high penetrance. RESULTS: Although there was evidence of clinical heterogeneity between the families, the duration of symptoms directly correlated with the severity of disease. The computer simulations indicated that 3 of the 4 pedigrees had enough power to generate a significant linkage result in a total genome search with highly polymorphic markers. CONCLUSIONS: This study confirms the frequent coexistence of ET and dystonia in individual families. Computer simulations can be used to determine the power of the family to detect a linked marker. Identification of the defective gene(s) will enable a better understanding and classification of these common movement disorders.

Aged↗
PubMed1997

Frataxin fracas.

Explore the source record for details and available documents.

Female↗
PubMed1997

Molecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions.

A male child with multiple congenital anomalies initially was clinically diagnosed as having Smith-Lemli-Opitz syndrome (SLOS). Subsequent cytogenetic studies revealed an interstitial deletion of 17p11.2, which is associated with Smith-Magenis syndrome (SMS). Biochemical studies were not supportive of a diagnosis of SLOS, and the child did not display the typical SMS phenotype. The father's karyotype showed a paracentric inversion of 17p, with breakpoints in p11.2 and p13.3, and the same inversion was also found in two of the father's sisters. FISH analyses of the deleted and inverted 17p chromosomes indicated that the deletion was similar to that typically seen in SMS patients and was found to bracket the proximal inversion breakpoint. Available family members were genotyped at 33 polymorphic DNA loci in 17p. These studies determined that the deletion was of paternal origin and that the inversion was of grandpaternal origin. Haplotype analysis demonstrated that the 17p11.2 deletion arose following a recombination event involving the father's normal and inverted chromosome 17 homologues. A mechanism is proposed to explain the simultaneous deletion and apparent "reinversion" of the recombinant paternal chromosome. These findings have implications for prenatal counseling of carriers of paracentric inversions, who typically are considered to bear minimal reproductive risk.

Abnormalities, Multiple↗
PubMed1996

Mosaicism for del(17)(p11.2p11.2) underlying the Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with deletion of band p11.2 of chromosome 17. The deletion is typically detected by high-resolution cytogenetic analysis of chromosomes from peripheral lymphocytes. Fluorescence in situ hybridization (FISH) has been previously used to rule out apparent mosaicism for del(17)(p11.2p11.2) indicated by routine cytogenetics. We now report mosaicism for del(17)(p11.2p11.2) in a child with SMS. The mosaicism had gone undetected during previous routine cytogenetic analysis. FISH analysis of peripheral lymphocytes as well as immortalized lymphoblasts using markers from 17p11.2 revealed that approximately 60% of cells carried the deletion. To our knowledge, this is the first case of SMS associated with mosaicism for del(17)(p11.2p11.2).

Abnormalities, Multiple↗
PubMed1996

Association study of schizophrenia and the dopamine D3 receptor gene locus in two independent samples.

Using a case-control design, an association of schizophrenia with the dopamine D3 receptor gene (D3RG) locus was investigated. Initial analysis of pooled results from published studies revealed a significant excess of individuals homozygous for either allele among the patients. The association was next tested in two cohorts ascertained independently at Pittsburgh, Pennsylvania and at Houston, Texas. The Pittsburgh sample was comprised of patients with schizophrenia (DSM-III-R) (n = 130). The controls belonged to two groups: adults screened for the absence of substance abuse or major psychiatric illness (n = 128), and neonates (n = 160). Multivariate analysis suggested an association with allele 1 of the biallelic D3RG polymorphism in comparison with the adult, but not the neonatal, controls. The association was most marked among Caucasian patients with a family history of schizophrenia (odds ratio 13.69, confidence intervals 1.80, 104.30). Survival analysis suggested an earlier age of onset among male patients homozygous for allele 2. The Houston cohort included Caucasian patients with schizophrenia or schizoaffective disorder (DSM-III-R criteria, n = 50), and normal controls matched for gender (n = 51). In this group, no significant associations were noted among all the patients or among subgroups of patients based on family history or age of onset. Possible reasons for the discordant results are discussed.

Adult↗
PubMed1996

Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion.

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

Alleles↗
PubMed1996

Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients.

We have used bivariate flow karyotyping to quantify the deletions involving chromosome 17 in sixteen patients with Smith-Magenis syndrome (SMS). The fluorescence intensities of mitotic chromosomes stained with Hoechst 33258 and chromomycin were quantified in a dual-beam flow cytometer. For each patient, the position of the peak representing the deleted chromosome 17 was compared to those of the normal homologs of an unaffected parent. The patients could be classified into four groups based on the size of their deletions. The deletions ranged from approximately 9-10 Mb (approximately 10-11% of the chromosome) to below the detection limit of the technique (2 Mb). Different deletion sizes were detected among patients whose high-resolution banding results were similar. Some deletions detected by banding were not detected by flow analyses. Deletion estimates are largely consistent with the results of molecular analyses. Patients with larger deletions that extend into band 17p 12 have abnormal electrophysiologic studies of peripheral nerves. Deletion size does not appear to correlate with the degree of mental retardation, presence of behavioral abnormalities, craniofacial anomalies or common skeletal findings in SMS. By identifying patients with varying deletion sizes, these data will aid the construction of a long-range deletion-based map of 17p11.2 and identification of the genes involved in this syndrome.

Abnormalities, Multiple↗
PubMed1996

Regulation of the hypoxanthine phosphoribosyltransferase gene: in vitro and in vivo approaches.

The hypoxanthine phosphoribosyltransferase (HPRT) locus is a constitutively expressed housekeeping gene characterized by a notably higher level of expression in the mammalian brain. The enzyme it encodes is key to purine salvage in humans and is the basis for the X-linked recessive disorder, Lesch-Nyhan syndrome (LNS). Methylation in the promoter plays a critical, if not fully understood, role in transcriptional silencing of the locus on the inactive chromosome, possibly by conferring structural stability. In vivo footprinting assays of the promoter region have shown protein interaction with multiple Spl-binding sites, a possible AP2 site, and a potentially novel binding site. In vitro studies of HPRT promoter deletion constructs have identified a minimal promoter element necessary for maximal transcription and a position-dependent, orientation-independent repressor element (HPRT-NE) that functions on heterologous promoters. Regulatory intron elements have also been observed. Studies on transgenic mice bearing HPRT promoter constructs have shown that the minimal promoter element is insufficient for in vivo expression and that HPRT-NE is responsible for conferring neuronal specificity. HPRT-mice possess metabolic defects similar to LNS patients, but fail to develop human behavioral abnormalities, perhaps because of species differences in purine metabolism. A neuronal-specific protein complex appears to be necessary for activator function of HPRT-NE, while a ubiquitously expressed complex may be responsible for repression. Sequence analysis Indicates that the latter complex may depend on the multifunctional transcription factor YY1 for binding. A fuller understanding of HPRT gene regulation will hopefully provide insight into the transcriptional mechanisms controlling the expression of housekeeping and brain-specific genes.

Animals↗
PubMed1996

Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.

Abnormalities, Multiple↗
PubMed1995

Mapping of the congenital generalized hypertrichosis locus to chromosome Xq24-q27.1.

Congenital generalized hypertrichosis (CGH) is a rare, fully penetrant X-linked dominant trait previously described in a single, multigenerational Mexican family. CGH is a visually striking phenotype characterized by excessive facial and upper torso hair in males and by less severe asymmetric hairiness in females. We have found significant evidence for linkage with several markers from the long arm of the X chromosome. Recombinant chromosomes place the CGH gene within a 22 cM interval between DXS425 and DXS1227 in Xq24-Xq27.1. The localization of a gene for CGH represents the first step towards the isolation of genes involved in hair growth pattern, particularly those involved in restriction of areas in humans.

Child↗
PubMed1995

The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable multiple congenital anomaly/mental retardation syndrome associated with deletion of chromosome 17p11.2. Here we report the identification of a novel gene encoding a human microfibril-associated glycoprotein (MFAP4), which has been mapped to the SMS region. A full-length cDNA corresponding to this gene has been sequenced, and reveals a coding region of 255 amino acids. MFAP4 has a fibrinogen-like domain and shares a high level of sequence homology to a fragment of a bovine 36 kDa microfibril-associated glycoprotein. The N-terminus of the protein bears an Arg-Gly-Asp sequence that serves as the ligand motif for cell surface receptor integrin. These structural features of MFAP4 suggest that it is an extracellular matrix protein involved in cell adhesion or intercellular interactions. Deletion analysis has been conducted on 31 SMS patients by polymerase chain reaction and Southern analysis of somatic cell hybrids retaining the del(17)(p11.2) chromosome or by fluorescence in situ hybridization. The MFAP4 locus is deleted in 30 of 31 SMS patients. Thus, the function of this gene must be considered in the pathogenesis of SMS. Given our previous hypothesis that SMS is a contiguous gene syndrome, complete and exhaustive definition of the critical deletion interval and a thorough phenotype-genotype correlation is required to demonstrate the role and importance of the MFAP4 gene in SMS.

Abnormalities, Multiple↗
PubMed1995

Mapping of genes predisposing to idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Twin and family studies suggest that genetic factors play a key part in IGE. A multilocus model appears to best fit the observed inheritance patterns. Mapping of IGE-related genes has been previously attempted using parametric methods, with conflicting results. In particular, recent evidence argues both for and against a chromosome 6p locus (EJM1) for juvenile myoclonic epilepsy, a subtype of IGE. We have approached the problem of mapping IGE loci using non-parametric methods, which have recently been successful for other complex diseases. No evidence for linkage to chromosome 6p was obtained. However, we obtained evidence for involvement of a locus at chromosome 8q24, close to the marker D8S256. The same 8q24 region was previously implicated in families with benign neonatal familial convulsions (BNFC), a generalized epilepsy syndrome that is inherited as a simple dominant mendelian trait. There is an apparent conserved syntenic group of genes in human 8q24 and a region of mouse chromosome 15, which harbors the stargazer (stg) locus. Homozygous mutant mice at the stg locus show a form of generalized epilepsy that resembles human absence epilepsy. Our findings may have implications for a locus on 8q24 predisposing to IGE.

Chromosome Mapping↗
PubMed1995

Ubiquitous and neuronal DNA-binding proteins interact with a negative regulatory element of the human hypoxanthine phosphoribosyltransferase gene.

The hypoxanthine phosphoribosyltransferase (HPRT) gene is constitutively expressed at low levels in all tissues but at higher levels in the brain; the significance and mechanism of this differential expression are unknown. We previously identified a 182-bp element (hHPRT-NE) within the 5'-flanking region of the human HPRT (hHPRT) gene, which is involved not only in conferring neuronal specificity but also in repressing gene expression in nonneuronal tissues. Here we report that this element interacts with different nuclear proteins, some of which are present specifically in neuronal cells (complex I) and others of which are present in cells showing constitutive expression of the gene (complex II). In addition, we found that complex I factors are expressed in human NT2/D1 cells following induction of neuronal differentiation by retinoic acid. This finding correlates with an increase of HPRT gene transcription following neuronal differentiation. We also mapped the binding sites for both complexes to a 60-bp region (Ff; positions -510 to -451) which, when analyzed in transfection assays, functioned as a repressor element analogous to the full-length hHPRT-NE sequence. Methylation interference footprintings revealed a minimal unique DNA motif, 5'-GGAAGCC-3', as the binding site for nuclear proteins from both neuronal and nonneuronal sources. However, site-directed mutagenesis of the footprinted region indicated that different nucleotides are essential for the associations of these two complexes. Moreover, UV cross-linking experiments showed that both complexes are formed by the association of several different proteins. Taken together, these data suggest that differential interaction of DNA-binding factors with this regulatory element plays a crucial role in the brain-preferential expression of the gene, and they should lead to the isolation of transcriptional regulators important in neuronal expression of the HPRT gene.

Base Sequence↗