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J Kere

Publications and source records attributed to J Kere.

At least 91 records · Page 5Linked to original sources
PubMed1999

Ectodysplasin, a protein required for epithelial morphogenesis, is a novel TNF homologue and promotes cell-matrix adhesion.

In the mouse Tabby (Ta) mutant and human X-linked anhidrotic ectodermal dysplasia (EDA) syndrome development of several ectodermal organs such as hair, teeth, and sweat glands is impaired. The gene behind Tabby and EDA has been cloned, and several alternative transcripts have been isolated. The protein product named ectodysplasin had no obvious function or prominent homology to other known gene products apart from a short collagen-like sequence. We have isolated two novel Ta transcripts which are variants of the longest isoform of Tabby, named Ta-A. In situ hybridizations revealed Ta-A to be the major transcript in the developing embryo. It was detected in the endoderm of early embryos and subsequently in specific locations in the neuroepithelium and ectoderm. Unexpectedly, sequence analysis of the most C-terminal domain of Ta revealed that ectodysplasin is a novel member of the tumor necrosis factor (TNF) ligand superfamily. Mouse ectodysplasin was biochemically and functionally characterized, and shown to be a glycosylated, oligomeric type II membrane protein (N-terminus inside), all characteristics typical to TNF-like proteins. Members of the TNF family are critically involved in host defence and immune response often mediating either apoptosis or cell survival. Expression of Ta in several epithelial cell lines did not result in prominent changes in cell morphology and did not promote apoptosis. Instead, it was shown to promote cell adhesion to extracellular matrix, a function consistent with its postulated role in epithelial-mesenchymal interactions regulating the development of ectodermal appendages. Ectodysplasin is the first TNF-like signaling molecule described known to be required for epithelial morphogenesis.

Amino Acid Sequence↗
PubMed1999

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis.

Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma.

Adult↗
PubMed1999

Clinical and morphological correlations for transglutaminase 1 gene mutations in autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a group of inherited disorders of cornification in which progress has recently been made in the identification of pathogenic mechanisms causing the disease. Transglutaminase 1 (TGM1) has been found as a defective gene in a large fraction of patients with lamellar ichthyosis (LI), a severe inherited scaling disorder of the skin. We have previously performed molecular genetic studies of 38Finnish ARCI families and found six different mutations in 13 families of 38 (34%). In this study we compared the molecular genetic alterations with clinical and electron microscopic findings of these patients. Families were classified by electron microscopy in ichthyosis congenita (IC) types I, II, III, IV and a non-defined group. TGM 1 gene mutation was found in all of the IC type II and 1/3 of the IC type 1 families. Although electron microscopy is not always used to classify ARCI patients, it can distinguish groups which are parallel with molecular genetic findings. This finding might be useful in the classification of ARCI patients for further linkage studies. Clinically typical phenotype of the TGM1 mutation carrier includes large, thick, brownish scales, but ichthyosis of some of these patients tends to be milder.

Adolescent↗
PubMed1999

Ectodysplasin is a collagenous trimeric type II membrane protein with a tumor necrosis factor-like domain and co-localizes with cytoskeletal structures at lateral and apical surfaces of cells.

Anhidrotic ectodermal dysplasia (EDA) is a human genetic disorder of impaired ectodermal appendage development. The EDA gene encodes isoforms of a novel transmembrane protein, ectodysplasin. The sequence of the longest isoform includes an interrupted collagenous domain of 19 Gly-X-Y repeats and a motif conserved in the tumor necrosis factor (TNF)-related ligand family. In order to understand better the function of the ectodysplasin protein molecule and its domains, we have studied the processing and localization of wild-type and mutated isoforms in transfected human fetal kidney 293 and monkey kidney COS-1 cells. Similar to other members of collagenous membrane proteins and members of TNF-related ligands, ectodysplasin is a type II membrane protein and it forms trimers. The membrane localization of ectodysplasin is asymmetrical: it is found on the apical and lateral surfaces of the cells where it co-localizes with cytoskeletal structures. The TNF-like motif and cysteines found near the C-terminus are necessary for correct transport to the cell membrane, but the intracellular and collagenous domains are not required for the localization pattern. Our results suggest that ectodysplasin is a new member in the TNF-related ligand family involved in the early epithelial-mesenchymal interaction that regulates ectodermal appendage formation.

Amino Acid Sequence↗
PubMed1999

Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy.

The striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin, a giant molecule that contains several immunoglobulin (Ig)-like domains and associates with thin and thick filaments, and [alpha]-actinin, an actin cross-linking protein. Mutations in several sarcomeric and sarcolemmal proteins have been shown to result in muscular dystrophy and cardiomyopathy. On the other hand, the disease genes underlying several disease forms remain to be identified. Here we describe a novel 57 kDa cytoskeletal protein, myotilin. Its N-terminal sequence is unique, but the C-terminal half contains two Ig-like domains homologous to titin. Myotilin is expressed in skeletal and cardiac muscle, it co-localizes with [alpha]-actinin in the sarcomeric I--bands and directly interacts with [alpha]-actinin. The human myotilin gene maps to chromosome 5q31 between markers AFM350yB1 and D5S500. The locus of a dominantly inherited limb-girdle muscular dystrophy (LGMD1A) resides in an overlapping narrow segment, and a new type of distal myopathy with vocal cord and pharyngeal weakness (VCPMD) has been mapped to the same locus. The muscle specificity and apparent role as a sarcomeric structural protein raise the possibility that defects in the myotilin gene may cause muscular dystrophy.

Actinin↗
PubMed1999

Downregulated in adenoma gene encodes a chloride transporter defective in congenital chloride diarrhea.

Congenital chloride diarrhea (CLD) is a recessively inherited disorder characterized by massive loss of chloride in stool. We previously identified mutations in the downregulated in adenoma (DRA) gene in patients with CLD and demonstrated that DRA encodes an intestine-specific sulfate transporter. To determine whether DRA is an intestinal chloride transporter and how mutations affect transport, Xenopus oocytes were injected with wild-type and mutagenized DRA cRNA and uptake of Cl- and SO2-4 was assayed. Both Cl- and SO2-4 were transported by wild-type DRA and an outwardly directed pH gradient stimulated Cl- uptake, consistent with Cl-/OH- exchange. Among three mutants, C307W transported both anions as effectively as wild-type, whereas transport activity was lost in V317del and the double mutant identified in 32 of 32 Finnish CLD patients. We conclude that DRA is a chloride transporter defective in CLD and that V317del is a functional mutation and C307W a silent polymorphism.

Animals↗
PubMed1999

Genetic Disorders of Membrane Transport III. Congenital chloride diarrhea.

Congenital chloride diarrhea (CLD) is a recessively inherited disorder of intestinal electrolyte absorption that involves, specifically, Cl-/HCO-3 exchange. CLD is caused by mutations in a chromosome 7 gene, first known as DRA (for downregulated in adenoma). The disease occurs in all parts of the world but is more common in some populations with genetic founder effects. More than 20 mutations in the gene are known to date. The CLD (or DRA) gene encodes a transmembrane protein belonging to the sulfate transporter family with three known members in humans, all associated with a distinct genetic disease. Members of the gene family can transport other anions as well that may turn out to be physiologically more important than sulfate transport. The gene family is well conserved in many prokaryotic and eukaryotic species and is expected to be much larger than presently known.

Bacterial Proteins↗
PubMed1999

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.

ATP-Binding Cassette Transporters↗
PubMed1998

Genomic structure of the human congenital chloride diarrhea (CLD) gene.

Congenital chloride diarrhea (CLD) is caused by mutations in a gene which encodes an intestinal anion transporter. We report here the complete genomic organization of the human CLD gene which spans approximately 39kb, and comprises 21 exons. All exon/intron boundaries conform to the GT/AG rule. An analysis of the putative promoter region sequence shows a putative TATA box and predicts multiple transcription factor binding sites. The genomic structure was determined using DNA from several sources including multiple large-insert libaries and genomic DNA from Finnish CLD patients and controls. Exon-specific primers developed in this study will facilitate mutation screening studies of patients with the disease. Genomic sequencing of a BAC clone H_RG364P16 revealed the presence of another, highly homologous gene 3' of the CLD gene, with a similar genomic structure, recently identified as the Pendred syndrome gene (PDS).

Base Sequence↗
PubMed1998

22-Mb integrated physical and genetic map based on YAC/STS content spanning the interval DXS1125-DXS95 in human Xq12-q21.31.

A YAC/STS map has been assembled spanning 22 Mb across Xq12-q21.31, between markers DXS1125 and DXS95. In addition to the landmark loci for the X-inactivation center XIST and the ATRX, ATP7A, phosphoglycerate kinase, POU3F4, and choroideremia genes, the candidate disease gene regions for torsion dystonia 3 and two X-linked mental retardation syndromes are included. Also, the human voltage-dependent anion channel gene (HVDAC1) has been placed near DXS986. The current map incorporates 211 YACs from five different libraries, formatted with 185 STSs that comprise 26 genetic linkage markers, 60 newly-developed YAC-end STSs, and eight ESTs. The multiple clone coverage and average resolution of one STS per 120 kb provide resources for disease gene searches and are facilitating complete sequencing of the region.

Base Sequence↗
PubMed1998

Clustering of private mutations in the congenital chloride diarrhea/down-regulated in adenoma gene.

An inherited defect in intestinal anion exchange, congenital chloride diarrhea (CLD), was recently shown to be caused by mutations in the down-regulated in adenoma (DRA) gene. A three base pair deletion resulting in the loss of an amino acid valine (V317del) in the predicted CLD/DRA protein was shown to be responsible for all CLD cases in a Finnish founder population. Two additional mutations, H124L and 344delT, were found in Polish CLD patients. Here, we screened for additional mutations in a set of 14 CLD families of Polish, Swedish, North American, and Finnish origin using primers that allowed mutation searches directly from genomic DNA samples. We found eight novel mutations in the CLD/DRA gene. The mutations included two transversions, one transition, one insertion, and four small deletions. Of 11 sequence alterations detected so far, nine lie clustered in three short segments that are 49 bp, 39 bp, and 65 bp in size, respectively. These short segments span only 6.7% of the total cDNA length, suggesting functional importance or mutation-prone DNA regions of the corresponding CLD/DRA protein domains.

Amino Acid Sequence↗
PubMed1998

Genomic structure of the human ezrin gene.

The ERM proteins, ezrin, radixin, and moesin, act as linkers between the plasma membrane and actin cytoskeleton. They are involved in a variety of cellular functions, such as cell adhesion, migration, and the organization of cell surface structures, and are highly homologous, both in protein sequence and in functional activity, with merlin/schwannomin, a neurofibromatosis-2-associated tumor-suppressor protein. We report here the genomic structure and intron junction sequences of the human ezrin gene. Ezrin consists of 13 exons and spans approximately 24 kb genomic DNA. The coding parts of the exons range in size from 12 bp to 275 bp and the introns from 182 bp to 7 kb. The genomic structures of ezrin and moesin are highly conserved, suggesting their recent divergence. Radiation hybrid mapping has refined the location of ezrin to the interval between D6S442 and D6S281.

Amino Acid Sequence↗
PubMed1998

Verification of self-reported asthma and allergy in subjects and their family members volunteering for gene mapping studies.

Studies which aim at mapping genes contributing to the development of asthma and atopy demand that hundreds of patients and their family members be assessed. In Finland, the Social Insurance Institution (SII) grants substantial reimbursement for medication to all patients who meet diagnostic criteria of asthma, which include a history of asthmatic symptoms and a measured reversibility of bronchial obstruction. To recruit a large number of asthma patients efficiently in a short period of time, we took advantage of the national reimbursement procedure and retrospectively collective data on patients' medical history and lung function test results at the time of diagnosis. First, we wanted to investigate if the reimbursements could be regarded as objective verification for self-reported asthma. Altogether 335 adult self-reported asthma patients were evaluated, 87% of them were verified as having chronic asthma. Reimbursement for medication showed a sensitivity of 95% and a specificity of 76% for verified asthma. Second, we were interested to see if self-reported nasal allergic symptoms or self-reported physician diagnosed allergic rhinitis were sensitive and specific measures of allergy. The self-reported allergic nasal symptoms had a poor specificity (31% in the proband group and 59% in the family members group) when compared to the allergy screening test (Phadiatop). The best verification for self-reported asthma was achieved by combining the information on self-reported disease, granted reimbursement by the SII and the medical records. For allergies, the specificity of self-reporting was far too low to be used alone, and a positive allergy screening test together with relevant symptoms was chosen as a marker of allergy.

Adolescent↗
PubMed1998

Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait.

Congenital chloride diarrhea (CLD) is an inherited intestinal disorder caused by mutations in the down-regulated in adenoma gene. In Finland, the disease is prevalent because of a founder effect, and all but one of the CLD-associated chromosomes carry the same mutation, V317del. In Poland, another area with a high incidence of CLD, as many as seven different mutations have been detected so far. A third known cluster of CLD, around the Persian Gulf, has not been genetically studied. We studied the allelic diversity of CLD in Poland, in Saudi Arabia and Kuwait, and in three isolated families from North America and Hong Kong. Altogether, eight novel mutations were identified, making a total of 19 known CLD gene mutations. The Polish major mutation I675-676ins was found in 47% of the Polish CLD-associated chromosomes. Haplotype analysis and clustering of the I675-676ins mutation supported a founder effect and common ancestral origin. As in Finland, a major founder effect was observed in Arab patients: 94% of the CLD-associated chromosomes carried a nonsense mutation, G187X, which occurred in either a conserved ancestral haplotype or its derivative. Our data confirm that the same locus is mutated in all cases of CLD studied so far. In Poland, a relatively common founder mutation is likely to highlight a set of rare mutations that would very rarely produce homozygosity alone. This suggests that mutations in the CLD locus are not rare events. Although the disease is thought to be rare, undiagnosed patients may not be uncommon.

Chlorides↗
PubMed1998

The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats.

Anhidrotic ectodermal dysplasia (EDA) is an X-linked recessive disorder which affects ectodermal structures. A cDNA encoding a 135 amino acid protein with mutations in 5-10% of EDA patients has been reported. We have built up a complete splicing map of the EDA gene and characterized the longest and what most probably represents the full-length EDA transcript, EDA-A. It encodes a 391 amino acid transmembrane protein with a short collagenous domain, (Gly-X-Y)19, and is highly homologous to the protein mutated in Tabby mice (Ta-A). Four new transcripts that code for truncated proteins lacking the collagenous domain were also detected. The splice variants show different expression patterns in eight tissues analyzed, suggesting a regulatory mechanism for gene expression. The EDA-A form of the protein is transported to the cell membrane and induces rounding of the cells, properties also associated with the 135 amino acid isoform. We have determined the genomic organization and the exon-intron boundaries of the EDA gene. SSCP analysis of the nine exons corresponding to EDA-A allowed the identification of mutations in 12 out of 15 EDA patients. Interestingly, three mutations removed either two or four of the Gly-X-Y repeats without interrupting the reading frame, thus suggesting a functional role for the collagenous domain. Our results will allow mutation diagnostics in the majority of patients.

Alternative Splicing↗