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Biomedical subjects

A M Bowcock

Publications and source records attributed to A M Bowcock.

At least 19 recordsLinked to original sources
PubMed2006

Psoriasis: genetic associations and immune system changes.

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a T-cell mediated 'Type-1' autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease.

Animals↗
PubMed2001

Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers.

A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides in its promoter region, and 3 (60%) of 5 primary breast tumors and 11 (79%) of 14 primary lung tumors were also found to be hypermethylated. Treatment of breast cancer MCF7 cells with 5'azacytidine and Trichostatin A resulted in expression of hSRBC, confirming DNA methylation as the mode of inactivation. Our results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human cancers, marking hSRBC as a candidate tumor suppressor gene.

Amino Acid Sequence↗
PubMed2001

Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies.

Approximately 2% of the Caucasian population is affected by psoriasis (PS); a chronic inflammatory skin disease triggered by both genetic and environmental risk factors. In addition to a major contribution from the HLA class I region, PS susceptibility loci have been mapped to a number of regions including 1q21, 3q21, 4qter, 14q31-q32, 17q24-q25, 19p13.3 and 20p. Some of these overlap with loci implicated in other autoimmune/inflammatory diseases. Global gene expression studies are beginning to provide insights into the etiology of these and other complex diseases. We used Affymetrix oligonucleotide arrays comprising approximately 12 000 known genes to initiate a more comprehensive analysis of the transcriptional changes that occur in involved and uninvolved skin of 15 psoriatic patients versus six normal controls. Expression levels of the transcripts detected on the arrays were first used to determine the relationship of samples to each other using hierarchical clustering. This analysis clearly differentiated involved psoriatic skin from uninvolved and normal skin. Clusters of differentially expressed genes with similar expression patterns in the same samples were then identified. Six out of 32 clusters contained a total of 177 transcripts that were differentially expressed in involved psoriatic skin versus normal skin. These differences were independent of the gender, age, skin site and HLA class I status of the patient. Ten of the 177 genes were also differentially expressed in uninvolved skin, and several mapped to regions previously shown to harbor psoriasis susceptibility loci.

Autoimmune Diseases↗
PubMed2001

Phenotypic heterogeneity in patients with familial partial lipodystrophy (dunnigan variety) related to the site of missense mutations in lamin a/c gene.

The lamin A/C (LMNA) gene has recently been reported to be mutated in familial partial lipodystrophy, Dunnigan variety (FPLD). We found mutations within exon 8 of LMNA (R482Q, R482W, and G465D) in 12 families with typical FPLD and in exon 11 (R582H) in 1 atypical family. To investigate phenotypic heterogeneity, we compared body fat distribution, using anthropometry and whole body magnetic resonance imaging, and metabolic parameters in women with atypical and typical FPLD. Compared with women with typical FPLD, the two sisters with atypical FPLD had less severe loss of sc fat from all the extremities and trunk and particularly from the gluteal region and medial parts of proximal thighs. Both types had similar excess of fat deposition in the neck, face, intraabdominal, and intermuscular regions. Women with atypical FPLD tended to have lower serum triglyceride and higher high density lipoprotein cholesterol concentrations. As exon 11 of LMNA does not comprise part of the lamin C-coding region, the R582H mutation affects only lamin A protein. Therefore, a unique phenotype of atypical FPLD may result from disrupted interaction of lamin A with other proteins and chromatin compared with typical FPLD, in which interaction of both lamins A and C may be disrupted.

Adipose Tissue↗
PubMed2000

Localization of susceptibility to familial idiopathic scoliosis.

STUDY DESIGN: Genome-wide linkage surveys in large multiplex families with apparent inherited idiopathic scoliosis. OBJECTIVE: To identify chromosomal loci encoding genes involved in susceptibility to idiopathic scoliosis by positional cloning. SUMMARY OF BACKGROUND DATA: Although the inheritance of idiopathic scoliosis most often exhibits a complex pattern, autosomal dominant inheritance can be identified in some families. Families exhibiting such an inheritance pattern present an opportunity to identify the predisposing gene(s) by positional cloning. METHODS: Probands having clinically relevant idiopathic scoliosis (50 degrees Cobb angle) from large multiplex families were identified. A curve of 15 degrees, made from standing posteroanterior radiographs, was required for a positive diagnosis. A genome-wide search in one large family (seven affected members) was conducted with 385 polymorphic microsatellite markers spaced at an approximate 10-cM resolution. Hot spots identified in this family were subsequently tested in a second large kindred. RESULTS: Maximum evidence of allele-sharing in affected individuals from the first family was detected for three loci on chromosomes 6p, distal 10q, and 18q with nonparametric lod scores of 1.42 (P = 0.020), 1.60 (P = 0.019), and 8.26 (P = 0.002), respectively. Evidence of allele-sharing was also detected in the second family at distal chromosome 10q (nonparametric lod score = 2.02; P = 0.033). CONCLUSIONS: These data indicate a limited number of genetic loci predisposing to idiopathic scoliosis.

Alleles↗
PubMed2000

Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies.

OBJECTIVE: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. BACKGROUND: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. METHODS: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. RESULTS: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. CONCLUSIONS: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.

Adolescent↗
PubMed2000

A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16.

OBJECTIVE: To use genetic linkage analysis to localize a gene for paroxysmal kinesigenic dyskinesia (PKD) in a three generation African-American kindred. BACKGROUND: PKD is a rare autosomal dominant disorder characterized by episodic choreiform or dystonic movements that are brought on or exacerbated by voluntary movement. There are individuals with the clinical features of PKD but with no family history of the disease, but whether these sporadic cases represent spontaneous mutations of PKD or have a distinct condition is unknown. METHODS: A genome-wide linkage scan of polymorphic microsatellites at 25 cM resolution was performed to localize a gene for PKD in one African-American kindred. Pairwise multipoint linkage analyses were performed at different penetrance estimates. RESULTS: Evidence for linkage of the kinesigenic form of paroxysmal dyskinesia to chromosome 16 was obtained. A maximum lod score of 4.40 at theta = 0 was obtained with D16S419. Critical recombinants place the PKD gene between D16S3100 and D16S771. CONCLUSIONS: A paroxysmal kinesigenic dyskinesia (PKD) locus lies within an 18 cM interval on 16p11.2-q11.2, between D16S3100 and D16S771. A gene for infantile convulsions with paroxysmal choreoathetosis has also been mapped to this region. These two regions overlap by approximately 6 cM. These two diseases could be caused by different mutations in the same gene or two distinct genes may lie within this region.

Black People↗
PubMed2000

Localization of a gene for familial recurrent arthritis.

OBJECTIVE: To localize the gene for familial recurrent arthritis via a genome-wide linkage scan in an extended kindred with the disease. METHODS: A 3-generation family in which 9 members were diagnosed with juvenile idiopathic arthritis (JIA) was ascertained. In this family the disease was of very early onset and included episodic inflammation leading to eventual destruction of joints, muscle, and skin. We treated this disorder as a distinct clinical entity that we have named "familial recurrent arthritis." A genome-wide linkage scan with polymorphic microsatellites at 10-15-cM resolution was initiated. RESULTS: The genome-wide scan generated a maximum 2-point logarithm of odds score with D15S211 (Zmax = 3.27 at thetamax = 0.0010). Haplotype reconstruction defined a candidate region of approximately 20 cM flanked proximally by D15S983 and distally by D15S127 on human chromosome 15. CONCLUSION: A gene for familial recurrent arthritis was localized to 15q22-24, as a result of a genome-wide linkage scan in a large, multiply affected kindred. Identification of the altered gene will provide insights into the pathogenesis of autoimmune joint destruction that is reminiscent of JIA.

Adult↗
PubMed2000

Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C.

Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.

Alleles↗
PubMed2000

Human population expansion and microsatellite variation.

Polymorphisms at di-, tri-, and tetranucleotide microsatellite loci have been analyzed in 14 worldwide populations. A statistical index of population expansion, denoted S(k), is introduced to detect historical changes in population size using the variation at the microsatellites. The index takes the value 0 at equilibrium with constant population size and is positive or negative according to whether the population is expanding or contracting, respectively. The use of S(k) requires estimation of properties of the mutation distribution for which we use both family data of Dib et al. for dinucleotide loci and our population data on tri- and tetranucleotide loci. Statistical estimates of the expansion index, as well as their confidence intervals from bootstrap resampling, are provided. In addition, a dynamical analysis of S(k) is presented under various assumptions on population growth or decline. The studied populations are classified as having high, intermediate, or low values of S(k) and genetic variation, and we use these to interpret the data in terms of possible population dynamics. Observed values of S(k) for samples of di-, tri-, and tetranucleotide data are compatible with population expansion earlier than 60,000 years ago in Africa, Asia, and Europe if the initial population size before the expansion was on the order of 500. Larger initial population sizes force the lower bound for the time since expansion to be much earlier. We find it unlikely that bottlenecks occurred in Central African, East Asian, or European populations, and the estimated expansion times are rather similar for all of these populations. This analysis presented here suggests that modern human populations departed from Africa long before they began to expand in size. Subsequently, the major groups (the African, East Asian, and European groups) started to grow at approximately same time. Populations of South America and Oceania show almost no growth. The Mbuti population from Zaire appears to have experienced a bottleneck during its expansion.

Animals↗
PubMed2000

JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.

X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic inflammation. Consistent with the allergic phenotype, analysis of two kindreds with XLAAD revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, we have identified in both kindreds mutations in JM2, a gene on Xp11.23 that encodes a fork head domain-containing protein. One point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain. The other mutation involves an in-frame, 3-bp deletion that is predicted to impair the function of a leucine zipper dimerization domain. Our results point to a critical role for JM2 in self tolerance and Th cell differentiation.

Amino Acid Sequence↗
PubMed1999

In vitro transformation of cell lines from human salivary gland tumors.

Explanted cells from salivary gland tumors are particularly difficult to propagate in vitro and not efficiently immortalized by agents such as simian virus 40. Human papillomavirus 16 (HPV16) has been widely used to transform cells of epithelial origin, but its use for salivary gland cell transformation has not been described. In this study, we employed viral constructs containing the E6/E7 genes of HPV16 to infect and stably transform 9 salivary gland tumor cell cultures. Four of the tumor cell cultures were derived from benign tumors and 5 from malignant tumors. All of the original cell cultures were diploid; however, 6 contained subpopulations of cells with structural abnormalities. All 9 cell cultures were successfully transformed, and 8 were immortalized. The resulting cell lines have decreased serum requirements, exhibit a high proliferation rate, are E6/E7-positive and form colonies in soft agar. Immuno-histochemical and molecular studies confirmed that the transformed cells were indeed epithelial/myoepithelial in origin. All of the transformed cell lines had a diploid or near-diploid karyotype, and 2 contained the original translocated chromosomes in all cells. Our report represents a new application of the E6/E7 system in immortalizing salivary gland cell cultures, resulting in retention of the cellular features found in the native tissue without a general destabilization of the karyotype. These types of tissue culture resources should prove useful for positional cloning and functional studies of genes involved in salivary gland oncogenesis.

Antigens, Differentiation↗
PubMed1999

Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei.

The Clock gene is an essential regulator of circadian rhythms. It encodes a member of the basic helix-loop-helix/PER-ARNT-SIM family of transcription factors known to play a central role in the control of diverse cellular events. Previously we described the functional identification and molecular isolation of the Clock gene in the mouse, its interaction with the BMAL1 protein, and the role of this complex as a transcriptional activator in the circadian pacemaker. Here, we report the cloning, exon organization, chromosomal location, and mRNA expression of the human CLOCK gene. The coding sequence of human CLOCK extends for 2538 bp and is 89% identical to its mouse ortholog; its deduced amino acid sequence is 846 residues long and is 96% identical to mouse CLOCK. Radiation hybrid mapping localized human CLOCK to the long arm of human chromosome 4 (4q12). Direct sequencing of a genomic CLOCK clone indicated that the coding sequence of human CLOCK extends over 20 exons and that its intron/exon organization is identical to that of the mouse ortholog. Northern blot analysis indicated widespread expression of two major transcripts of 8 and 10 kb, and in situ hybridization of human brain tissue revealed elevated expression of CLOCK mRNA in the suprachiasmatic nuclei, the locus of circadian control in mammals, and in the cerebellum. Comparison of cDNA clones revealed two single nucleotide polymorphisms in noncoding sequence flanking the CLOCK open reading frame. The central role of Clock in the organization of circadian rhythms suggests that it will be a useful candidate gene for genetic analyses of disorders associated with dysfunction of the circadian system.

Alleles↗
PubMed1999

Genomic structure, mapping, and expression analysis of the mammalian Lunatic, Manic, and Radical fringe genes.

The three members of the mammalian fringe gene family, Manic fringe (Mfng), Radical fringe (Rfng), and Lunatic fringe (Lfng), were identified on the basis of their similarity to Drosophila fringe (fng) and their participation in the evolutionarily conserved Notch receptor signaling pathway. Fringe genes encode pioneer secretory proteins with weak similarity to glycosyltransferases. Both expression patterns and functional studies support an important role for Fringe genes in patterning during embryonic development and an association with cellular transformation. We have now further characterized the expression and determined the chromosomal localization and genomic structure of the mouse Mfng, Rfng, and Lfng genes; the genomic structure and conceptual open reading frame of the human RFNG gene; and the refined chromosomal localization of the three human fringe genes. The mouse Fringe genes are expressed in the embryo and in adult tissues. The mouse and human Fringe family members map to three different chromosomes in regions of conserved synteny: Mfng maps to mouse Chr 15, and MFNG maps to human Chr 22q13.1 in the region of two cancer-associated loci; Lfng maps to mouse Chr 5, and LFNG maps to human Chr 7p22; Rfng maps to mouse Chr 11, and RFNG maps to human Chr 17q25 in the minimal region for a familial psoriasis susceptibility locus. Characterization of the genomic loci of the Fringe gene family members reveals a conserved genomic organization of 8 exons. Comparative analysis of mammalian Fringe genomic organization suggests that the first exon is evolutionarily labile and that the Fringe genes have a genomic structure distinct from those of previously characterized glycosyltransferases.

Animals↗
PubMed1999

A gene for congenital generalized lipodystrophy maps to human chromosome 9q34.

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.

Acanthosis Nigricans↗