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Biomedical subjects

N Lench

Publications and source records attributed to N Lench.

At least 19 recordsLinked to original sources
PubMed2001

Replication and extension studies of inflammatory bowel disease susceptibility regions confirm linkage to chromosome 6p (IBD3).

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine, commonly diagnosed as either ulcerative colitis (UC) or Crohn's disease (CD). Epidemiological studies have consistently shown that both genetic and environmental factors influence the pathogenesis of IBD. A number of genome scans have been conducted in cohorts of IBD families with affected sibling pairs (ASPs) to identify chromosomal regions that harbour IBD susceptibility genes. Several putative linked loci have been identified, including two loci on chromosomes 16 and 12, IBD1 and IBD2, which have subsequently been replicated by independent region-specific studies. We have conducted both a replication study on another linkage region, chromosome 6p (IBD3), and extension studies on two other regions, chromosomes 3p and 7q. Microsatellite markers across each region were genotyped in 284 IBD ASPs from 234 families. A nonparametric peak multipoint LOD score of 3.0 was observed near D6S291, replicating the previous linkage to chromosome 6p (IBD3). Nominal evidence of linkage was observed at both the 3p and 7q regions.

Chromosome Mapping↗
PubMed2000

Detection of a novel mutation in X-linked amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited disorders of defective enamel formation. The major protein involved in enamel formation, amelogenin, is encoded by a gene located at Xp22.1-Xp22.3. This study investigated the molecular defect producing a combined phenotype of hypoplasia and hypomineralization in a family with the clinical features and inheritance pattern of X-linked amelogenesis imperfecta (XAI). Genomic DNA was prepared from buccal cells sampled from family members. The DNA was subjected to the polymerase chain-reaction (PCR) in the presence of a series of oligonucleotide primers designed to amplify all 7 exons of the amelogenin gene. Cloning and sequencing of the purified amplification products identified a cytosine deletion in exon VI at codon 119. The deletion resulted in a frameshift mutation, introducing a premature stop signal at codon 126, producing a truncated protein lacking the terminal 18 amino acids. Identifying mutations assists our understanding of the important functional domains within the gene, and finding another novel mutation emphasizes the need for family-specific diagnosis of amelogenesis imperfecta.

Amelogenesis Imperfecta↗
PubMed1999

Gap junctions and connexin expression in the inner ear.

Several different recessive mutations in the connexin26 (Cx26; beta 2) gene have been associated with non-syndromic hereditary deafness. This suggests gap junctions are important to cochlear function. Numerous large gap junctions are present between adjacent supporting cells in both the vestibular and auditory sensory epithelia of the mature inner ear. In vestibular organs, Cx26 is highly expressed, but antibodies of Cx32 (beta 1) also label the supporting cells. In the organ of Corti of the cochlea, Cx26 is the predominant connexin isoform; neither Cx32 nor Cx43 (alpha 1) can be detected by immunohistochemistry. One role for gap junctions between supporting cells may be to provide a pathway for the rapid removal of ions away from the region of the sensory cells during transduction in order to maintain sensitivity. In the cochlea gap junctions are also associated with the basal cells of the stria vascularis, an ion-transporting epithelium that maintains a positive electrical potential in the potassium-rich endolymph fluid which bathes the apical surfaces of the sensory 'hair' cells and which is crucial for auditory transduction. Gap junctions are present between fibrocytes in the spiral ligament that underlies the stria vascularis, and between these fibrocytes and strial basal cells. During cochlear development, the initial formation and subsequent increase in size and number of gap junctions in the stria vascularis coincides with the initial generation and rise of the endocochlear potential. This and other evidence suggests that one role of gap junctions in the cochlea is to provide a pathway for passage of ions to maintain endolymph and, thus, auditory acuity. Mutations to Cx26 could, therefore, disrupt this ion circulation, resulting in deafness.

Amino Acid Sequence↗
PubMed1999

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

Aggressive Periodontitis↗
PubMed1995

Amelogenesis imperfecta in triplets: a unique family record.

A unique family is recorded in which triplets were observed with the hypomaturation type of amelogenesis imperfecta. A simple technique of DNA analysis showed that two of the more severely affected triplets were monozygotic and the third less severely affected triplet dizygotic.

Alleles↗
PubMed1995

Prostate-specific membrane antigen: evidence for the existence of a second related human gene.

Prostate-specific membrane antigen (PSM) is a glycoprotein recognised by the prostate-specific monoclonal antibody 7E11-C5, which was raised against the human prostatic carcinoma cell line LNCaP. A cDNA clone for PSM has been described. PSM is of clinical importance for a number of reasons. Radiolabelled antibody is being evaluated both as an imaging agent and as an immunotherapeutic in prostate cancer. Use of the PSM promoter has been advocated for gene therapy applications to drive prostate-specific gene expression. Although PSM is expressed in normal prostate as well as in primary and secondary prostatic carcinoma, different splice variants in malignant tissue afford the prospect of developing reverse transcription-polymerase chain reaction (RT-PCR)-based diagnostic screens for the presence of prostatic carcinoma cells in the circulation. We have undertaken characterisation of the gene for PSM in view of the protein's interesting characteristics. Unexpectedly, we have found that there are other sequences apparently related to PSM in the human genome and that PSM genomic clones map to two separate and distinct loci on human chromosome 11. Investigation of the function of putative PSM-related genes will be necessary to enable us to define fully the role of PSM itself in the development of prostatic carcinoma and in the clinical management of this malignancy.

Antigens, Neoplasm↗
PubMed1995

Nance-Horan syndrome: a contiguous gene syndrome involving deletion of the amelogenin gene? A case report and molecular analysis.

DESIGN: A case of Nance-Horan syndrome in a male is presented, with some features of the condition in his carrier mother and her mother. It is proposed that Nance-Horan syndrome might be a contiguous gene syndrome mapping to chromosome Xp21.2-p22.3. SETTING: The proband had congenital cataract microphthalmia and dental abnormalities including screwdriver shaped incisors and evidence of enamel pitting hypoplasia. The region Xp21.2-p22.3 also contains the tooth enamel protein gene, amelogenin (AMGX). RESULTS: Using molecular genetic techniques, we have shown that there is no evidence that the AMGX gene is deleted in this case of the Nance-Horan syndrome.

Abnormalities, Multiple↗
PubMed1988

Simple non-invasive method to obtain DNA for gene analysis.

A technique is described which demonstrates that sufficient human DNA for direct gene analysis can be isolated from buccal epithelial cells obtained by mouthwash. This procedure is much simpler and cheaper than existing methods and, combined with DNA amplification by polymerase chain reaction, should allow community screening for carrier status for single gene defects such as cystic fibrosis.

Cheek↗
PubMed1988

Detection of a rare-cutter RFLP in a CpG-rich island near the cystic fibrosis locus.

The probe pCS.7, isolated from an HpaII tiny fragments (HTF) island and tightly linked to the mutation causing cystic fibrosis (CF), detects a polymorphism with the rare-cutter restriction enzyme BssHII. In a single digest, the resulting restriction fragment length polymorphism (RFLP) cannot be detected by either conventional or pulse-field gel electrophoresis. A double digest with BssHII in conjunction with a six-cutter restriction enzyme that does not recognize a site containing a CpG dinucleotide enables the probe to be used routinely for prenatal diagnosis and carrier exclusion. This strategy can be used to identify polymorphisms in HTF islands.

Alleles↗
PubMed1988

Refined linkage map of chromosome 7 in the region of the cystic fibrosis gene.

The genetic map in the region of human chromosome 7 that harbors the gene for cystic fibrosis (CF) has been refined by multilocus linkage studies in an expanded database including a large set of normal families. Six loci known to be linked to CF were examined: MET, an oncogene; COL1A2, collagen, TCRB, T-cell-receptor beta polypeptide; and three arbitrary loci--D7S8, D7S13, and D7S16--defined by probes pJ3.11, pB79a, and p7C22, respectively. The gene order with greatest statistical support is COL1A2-D7S13-D7S16-MET-D7S8-TCRB. Linkage analysis in families segregating for CF suggested that the most likely location of the CF gene on this map is between MET and D7S8.

Chromosome Mapping↗
PubMed1987

Progress towards construction of a total restriction fragment map of a human chromosome.

We present an approach to the construction of an overlapping restriction fragment map of a single human chromosome. A genomic cosmid library genome was constructed from a mouse-human hybrid cell line containing chromosome 17 as its only human genetic component. Cosmids containing human inserts were isolated by hybridisation to a human Alu sequence. DNAs from ninety-six randomly chosen cosmids were digested with either EcoRI or HindIII, end-labelled with 35S-dATP and analysed using agarose gel electrophoresis. Comparison of the restriction fragment patterns revealed two pairs of overlapping clones, that were confirmed by cross-hybridization of the overlapping fragments. The two pairs of cosmids both mapped to human chromosome 17, as shown by hybridization to a panel of somatic cell hybrids. These data demonstrate that the generation of an overlapping cosmid map along a human chromosome is feasible, representing an intermediate step towards the complete sequencing of a human chromosome.

Animals↗
PubMed1987

The application of molecular genetics to the study of the basic defect causing cystic fibrosis.

The first linkage to CF was demonstrated to the enzyme paroxonase, a classical protein polymorphism, by the Copenhagen group. This was followed quickly by six cloned DNA sequences: pJ3.11, 7C22, COL1A2 and TCRB (St. Mary's), 917 (Toronto) and met (Salt Lake City). Both pJ3.11 and met are very close genetically to the CF mutation, and can be used for carrier detection and antenatal diagnosis in many informative families where there is a CF child. There is no evidence for heterogeneity of the CF locus. The collection of markers surrounding the CF locus is now sufficient to permit attempts to be made to isolate the defective gene using a combination of chromosome-mediated gene transfer, pulse field gel electrophoresis, NotI junction libraries, cosmid mapping and chromosome walking techniques.

Chromosome Mapping↗