ABSTRACT
Killer cell immunoglobulin-like receptors (KIRs) belong to a diverse family of natural killer (NK) cell receptors recognizing human leukocyte antigen (HLA) class I molecules. Due to this functional link, KIR molecules are expected to display a high polymorphism, such as their HLA ligands. Moreover, many studies conducted in mouse and human models have shown that NK-KIR receptors play an important role in haematopoietic stem cell transplantation (HSCT). A beneficial impact of peculiar KIR ligand (HLA) mismatching has been reported suggesting a role to this combinatory HLA-KIR polymorphism. It is thus important to investigate KIR diversity in various human populations. To this end, we used polymerase chain reaction-sequence-specific primers to evaluate KIR gene in five selected populations (France, Guadeloupe, Senegal, Finland and Réunion). Genotypic and haplotypic frequencies were computed, as well as genetic distances and dendrogram (phylip package). These data illustrate the genetic relationship of these five populations through the KIR polymorphism. Results revealed a wide diversity in KIR gene frequencies in Guadeloupe and Réunion, and a high specificity in Senegal. The obtained dendrogram indicated small genetic distances between France, Guadeloupe and Réunion as well as between France and Finland. Senegal showed a distant genetic relationship with the other countries and, interestingly, an inverted ratio of coding/non-coding (KIR2DS4/1D) alleles compared with Caucasians. These data expose the broad diversity in KIR genes worldwide and show that KIR genes are pertinent tools in human population genetics. If the role of KIR donor-recipient incompatibilities is confirmed, KIR diversity according to ethnicity should be taken into account during the selection of HSCT donors.
Subject(s)
Alleles , Gene Frequency/genetics , Polymorphism, Genetic/genetics , Receptors, Immunologic/genetics , Female , Finland , France , Gene Frequency/immunology , Genetics, Population/methods , Genotype , Guadeloupe , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Male , Polymorphism, Genetic/immunology , Receptors, Immunologic/immunology , Receptors, KIR , Reunion , SenegalABSTRACT
BACKGROUND: Acrodermatitis enteropathica is a rare autosomal recessive disorder, caused by impaired absorption of zinc from the gastrointestinal tract. Symptoms of acrodermatitis enteropathica occur within the first few months after birth and tend to appear shortly after discontinuation of breast-feeding. We report a breast-fed infant with acrodermatitis enteropathica. CASE REPORT: A full term, 4-month-old girl, consulted in dermatologic department for persistent and refractory anogenital lesions since the age of 1 month, with progressive erythematous, vesiculous and squamous lesions, sometimes erosive in a peri orificial and acral pattern. She was calm and healthy baby. She was breast feeding. The diagnosis of acrodermatitis enteropathica was confirmed by decreased plasma zinc level (14 microg/100 ml). Breast milk zinc levels was low (46 microg/100 ml), as plasma zinc level of the mother (94 microg/100 ml). A genetic study showed that she was homozygous for the mutation, whereas her brother and parents were heterozygous. She was given zinc sulphate, and her condition has improved significantly. DISCUSSION: Acrodermatitis enteropathica is characterized by a characteristic clinical feature and the diagnosis is confirmed by decreased plasma zinc level. Acrodermatitis enteropathica in exclusively breast fed infant is rare, it was essentially reported in premature babies. Our case report is particular because it's concerning a full-term breast-fed infant, with zinc deficiency in breast milk and mother's decreased plasma zinc level.
Subject(s)
Acrodermatitis/genetics , Acrodermatitis/pathology , Breast Feeding , Astringents/therapeutic use , DNA Mutational Analysis , Female , Humans , Infant , Treatment Outcome , Zinc Sulfate/therapeutic useSubject(s)
Carcinoma, Medullary/genetics , Genetic Predisposition to Disease , Germ Cells , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/genetics , Transfection , Base Sequence , DNA Primers , Humans , Proto-Oncogene Mas , Proto-Oncogene Proteins c-retABSTRACT
The zinc transporter gene SLC30A4, located on chromosome 15q15-q21, has previously been reported to show altered expression patterns in post mortem analysis of the brains of schizophrenic patients. As a positional candidate we investigated SLC30A4 in the chromosome 15q15-linked schizophrenic phenotype periodic catatonia (MIM 605419), by means of a systematic mutation screening in affected individuals from exceptionally large pedigrees with perfect co-segregation of a chromosomal segment between marker D15S1042 and D15S659 in all affected individuals. The mutation scan revealed no genetic variants within the coding and the putative promoter region of SLC30A4 and, thus, excludes a genetic association of SLC30A4 with catatonic schizophrenia.
Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Chromosomes, Human, Pair 15/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Schizophrenia, Catatonic/genetics , Brain/metabolism , Brain/physiopathology , Chromosome Mapping , DNA Mutational Analysis , Genetic Markers , Genetic Testing , Humans , Promoter Regions, Genetic/genetics , Schizophrenia, Catatonic/metabolism , Zinc/metabolismABSTRACT
In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits. Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies. Two patients were diagnosed with vestibular pathology. All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis. No individual in this family met diagnostic criteria for any previously described clinical syndrome. A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein. JAG1 is a cell-surface ligand in the Notch signaling pathway. Mutations in JAG1 have been identified in patients with Alagille syndrome. Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred, which demonstrates that mutation in JAG1 can cause hearing loss.
Subject(s)
Abnormalities, Multiple/genetics , Arcus Senilis/genetics , Deafness/genetics , Heart Defects, Congenital/genetics , Proteins/genetics , Amino Acid Sequence , Amino Acid Substitution , Animals , Arcus Senilis/congenital , Base Sequence , Calcium-Binding Proteins , Cysteine/chemistry , DNA/genetics , Deafness/congenital , Female , Genes, Dominant , Humans , Intercellular Signaling Peptides and Proteins , Jagged-1 Protein , Male , Membrane Proteins , Molecular Sequence Data , Mutation , Pedigree , Protein Structure, Tertiary , Proteins/chemistry , Sequence Homology, Amino Acid , Serrate-Jagged ProteinsABSTRACT
BACKGROUND: The SCN5A gene encoding the human cardiac sodium channel alpha subunit plays a key role in cardiac electrophysiology. Mutations in SCN5A lead to a large spectrum of phenotypes, including long-QT syndrome, Brugada syndrome, and isolated progressive cardiac conduction defect (Lenègre disease). METHODS AND RESULTS: In the present study, we report the identification of a novel single SCN5A missense mutation causing either Brugada syndrome or an isolated cardiac conduction defect in the same family. A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the sodium channel protein. Among 45 family members, 13 were carrying the G1406R SCN5A mutation. Four individuals from 2 family collateral branches showed typical Brugada phenotypes, including ST-segment elevation in the right precordial leads and right bundle branch block. One symptomatic patient with the Brugada phenotype required implantation of a cardioverter-defibrillator. Seven individuals from 3 other family collateral branches had isolated cardiac conduction defects but no Brugada phenotype. Three flecainide test were negative. One patient with an isolated cardiac conduction defect had an episode of syncope and required pacemaker implantation. An expression study of the G1406R-mutated SCN5A showed no detectable Na(+) current but normal protein trafficking. CONCLUSIONS: We conclude that the same mutation in the SCN5A gene can lead either to Brugada syndrome or to an isolated cardiac conduction defect. Our findings suggest that modifier gene(s) may influence the phenotypic consequences of a SCN5A mutation.
Subject(s)
Heart Conduction System/pathology , Sodium Channels/genetics , Animals , COS Cells , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Electrocardiography , Family Health , Female , France , Green Fluorescent Proteins , Heart Block/genetics , Heart Block/physiopathology , Heart Conduction System/metabolism , Heart Conduction System/physiopathology , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Membrane Potentials/physiology , Microscopy, Confocal , Microscopy, Fluorescence , Mutation , Mutation, Missense , NAV1.5 Voltage-Gated Sodium Channel , Pedigree , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , SyndromeABSTRACT
In many haematological diseases, and more particularly in B-cell chronic lymphocytic leukaemia (B-CLL), the existence of a tumour suppressor gene located within the frequently deleted region 13q14.3, has been put forward. A wide candidate region spanning from marker D13S273 to D13S25 has been proposed and an extensive physical map has been constructed by several teams. In this study, we sequenced a minimal core deleted region that we have previously defined and annotated it with flanking available public sequences. Our analysis shows that this region is gene-poor. Furthermore, our work allowed us to identify new alternative transcripts, spanning core regions, of the previously defined candidate genes DLEU1 and DLEU2. Since their putative involvement in B-CLL was controversial, our present study provide support for reconsidering the DLEU1 and DLEU2 genes as B-CLL candidate genes, with a new definition of their organisation and context.
Subject(s)
B-Lymphocytes/metabolism , Genes, Tumor Suppressor , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Sequence Deletion/genetics , Alternative Splicing/genetics , Base Sequence , Chromosome Mapping , Databases, Nucleic Acid , Exons/genetics , Expressed Sequence Tags , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Repetitive Sequences, Nucleic Acid/genetics , Sequence Analysis, DNAABSTRACT
Using allele-specific amplification method (ARMS), a highly sensitive one-stage allele-specific PCR, we have evaluated the incidence of NRAS and KRAS2 activating mutations (codons 12, 13, and 61) in 62 patients with either monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM), primary plasma-cell leukemia (P-PCL), and also in human myeloma cell lines (HMCL). NRAS and/or KRAS2 mutations were found in 54.5% of MM at diagnosis (but in 81% at the time of relapse), in 50% of P-PCL, and in 50% of 16 HMCL. In contrast, the occurrence of such mutations was very low in MGUS and indolent MM (12.50%). Of note, KRAS2 mutations were always more frequent than NRAS. The validity of the technique was assessed by direct sequencing of cell lines and of some patients. Multiple mutations found in two patients were confirmed by subcloning exon PCR amplification products, testing clones with our method, and sequencing them. Thus, these early mutations could play a major role in the oncogenesis of MM and P-PCL.
Subject(s)
Genes, ras/genetics , Leukemia, Plasma Cell/genetics , Multiple Myeloma/genetics , Alleles , Base Sequence , DNA Mutational Analysis , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Gene Frequency , Humans , Leukemia, Plasma Cell/diagnosis , Multiple Myeloma/diagnosis , Mutation , Polymerase Chain Reaction/methods , Tumor Cells, CulturedABSTRACT
Slc30a4 is the fourth and last identified member of a mammalian proteins family presumably involved in the cellular transport of zinc, solute carrier family 30. The murine homologue of the human SLC30A4 gene has previously been investigated and found responsible for the lm, a phenotype due to zinc deficiency. According to the strong homology between mouse and human SLC30A4 coding sequences, and to the very similar clinical features encountered in the murine lm and in human acrodermatitis enteropathica, SLC30A4 has appeared to us to be a good candidate for acrodermatitis enteropathica. Here we detail the genomic structure of human SLC30A4 together with its localization on chromosome 15q15-q21. We also report the mutational analysis of human SLC30A4 in ten families with acrodermatitis enteropathica, which enabled us to exclude this gene from any involvement in the disorder of the patients examined.
Subject(s)
Acrodermatitis/genetics , Carrier Proteins/genetics , Chromosomes, Human, Pair 15/genetics , Acrodermatitis/metabolism , Amino Acid Sequence , Base Sequence , Blotting, Northern , Cation Transport Proteins , Chromosome Mapping , Chromosomes, Artificial/genetics , DNA Mutational Analysis , DNA Primers/chemistry , Genetic Linkage , Humans , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Promoter Regions, Genetic , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Sequencing the complete factor IX gene of 2 sisters with hemophilia B with different phenotypes and no family history of hemorrhagic diathesis revealed a common 5' splice site mutation in intron 3 (T6704C) in both and an additional missense mutation (I344T) in one. The presence of dysfunctional antigen in the latter strongly suggested that these mutations are in trans. Neither mutation was found in leukocyte DNA from the asymptomatic parents, but the mother was in somatic mosaicism for the shared splice site mutation. This case illustrates the importance of defining the phenotype and considering somatic mosaicism in sporadic cases. It underlines the limitations of complete gene sequencing for the detection of mosaicism and has implication for genetic counseling. (Blood. 2000;96:1585-1587)
Subject(s)
Factor IX/genetics , Hemophilia B/genetics , Mosaicism , Adolescent , Female , Heterozygote , Humans , MutationABSTRACT
The variability at three microsatellites in the Cystic Fibrosis Transmembrane Conductance Regulator Gene (CFTR) locus has been studied for frequent mutations encountered in an isolated population of "Grande Brière", a small region located in Southern Brittany. Fluorescent multiplex PCR of these microsatellites were assayed in 16 Cystic Fibrosis (CF) families carrying 5 different mutations. The four most frequent haplotypes on df508 chromosomes were the same as those found in Northern France and Europe but the distribution of these haplotypes provides new enlightenment on the population origin of this insular community.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Genetics, Population , Microsatellite Repeats/genetics , DNA Mutational Analysis , France , Haplotypes , Humans , Pedigree , Polymerase Chain ReactionABSTRACT
The chromosomal region 13q14.3 is frequently deleted in B cell chronic lymphocytic leukemia (B-CLL) and it is supposed that a tumor suppressor gene, involved in this leukemogenesis, is located in this area. The first exons of two genes, Leu1 and Leu2, mapped in a minimally deleted 13q14.3 region, are systematically lost in B-CLL sharing a 13q14.3 deletion. These two genes have been proposed as strong tumor suppressor gene candidates. However, in a study on 15 13q14.3 deleted B-CLL, we found three patients in which this critical region was not involved. Because of these results and that no mutations were detected on the two genes in a previous study, we think that Leu1 and Leu2 can be excluded as tumor suppressor genes.
Subject(s)
CD5 Antigens/genetics , CD8 Antigens/genetics , Chromosome Deletion , Chromosomes, Human, Pair 13 , Genes, Tumor Suppressor , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Humans , Loss of Heterozygosity , Polymerase Chain ReactionABSTRACT
With 10 segregating sites (simple nucleotide polymorphisms) in the last intron (1089 bp) of the ZFX gene we have observed 11 haplotypes in 336 chromosomes representing a worldwide array of 15 human populations. Two haplotypes representing 77% of all chromosomes were distributed almost evenly among four continents. Five of the remaining haplotypes were detected in Africa and 4 others were restricted to Eurasia and the Americas. Using the information about the ancestral state of the segregating positions (inferred from human-great ape comparisons), we applied coalescent analysis to estimate the age of the polymorphisms and the resulting haplotypes. The oldest haplotype, with the ancestral alleles at all the sites, was observed at low frequency only in two groups of African origin. Its estimated age of 740 to 1100 kyr corresponded to the time to the most recent common ancestor. The two most frequent worldwide distributed haplotypes were estimated at 550 to 840 and 260 to 400 kyr, respectively, while the age of the continentally restricted polymorphisms was 120 to 180 kyr and smaller. Comparison of spatial and temporal distribution of the ZFX haplotypes suggests that modern humans diverged from the common ancestral stock in the Middle Paleolithic era. Subsequent range expansion prevented substantial gene flow among continents, separating African groups from populations that colonized Eurasia and the New World.
Subject(s)
DNA-Binding Proteins/genetics , Genealogy and Heraldry , Haplotypes , Introns , Polymorphism, Genetic , Humans , Kruppel-Like Transcription Factors , Male , Models, Genetic , Time Factors , Transcription Factors , X ChromosomeABSTRACT
We report the characterization of a new gene mapped at chromosome band 13q14.3 telomeric to the retinoblastoma gene. This gene, designated CHC1L (for chromosome condensation 1-like), is composed of 14 exons spanning 30 kb of genomic DNA and encodes a ubiquitously expressed 3-kb mRNA. The N-terminal half of the deduced amino acid sequence shows strong homology with the seven tandem repeat structure of the regulator of chromosome condensation RCC1, which acts as a guanine nucleotide exchange factor (GEF) protein for the Ras-related GTPase Ran. CHC1L appears to be a new member of the RCC1-related GEF family.
Subject(s)
Cloning, Molecular , Proteins/genetics , Amino Acid Sequence , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 13/genetics , DNA, Complementary , Guanine Nucleotide Exchange Factors , Humans , Molecular Sequence Data , Proteins/chemistry , Proteins/metabolism , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Sequence Alignment , Tumor Cells, Cultured , ras Guanine Nucleotide Exchange FactorsABSTRACT
Carl Wilhelm Naundorff was buried in 1845 in Delft as Louis Charles, Duc de Normandie, 'Louis XVII'. However, the son of Louis XVI and Marie-Antoinette-Louis XVII--officially died in the Temple of Paris in 1795. In order to resolve the identity of Naundorff, mitochondrial DNA (mtDNA) D-loop sequences of his remains were compared with the sequences obtained from the hairs of two sisters of Marie-Antoinette, Marie-Antoinette herself, and with the sequences obtained from DNA samples of two living maternal relatives. The mtDNA sequence of a bone sample from Naundorff showed two nucleotide differences from the sequences of the three sisters and four differences from the sequences of living maternal relatives. Based on this evidence it becomes very unlikely that Naundroff is the son of Marie-Antoinette.
Subject(s)
DNA, Mitochondrial/genetics , Famous Persons , Forensic Anthropology , Base Sequence , Consensus Sequence , Female , France , Humans , Male , Pedigree , Polymorphism, Genetic , Y ChromosomeABSTRACT
An expression map containing 48 ESTs was constructed to identify a tumor-suppressor gene involved in B-cell chronic lymphocytic leukemia (B-CLL), which was previously assigned to chromosome band 13q14.3 close to genetic markers D13S25 and D13S319. Thirty-nine of these 48 ESTs, together with 11 additional ones listed in databases, were initially assigned to chromosome 13q14 between markers D13S168 and D13S176. Nine others have recently been located in the D13S319 region. Our results indicate that 48 of the 59 ESTs analyzed belong to a YAC contig of chromosome 13 band q14, and 22 are contained on YAC 933e9, which encompasses the B-CLL critical region. Ten of these 22 ESTs were accurately assigned on a PAC, BAC, and cosmid contig encompassing the smallest minimal deletion area described so far in B-CLL, and 20 were tested for their expression on 27 normal or tumor tissues. One EST appears to be a likely candidate for the tumor-suppressor gene involved in B-CLL.
Subject(s)
Chromosomes, Human, Pair 13/genetics , Gene Expression Regulation, Neoplastic/genetics , Genes, Tumor Suppressor/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Chromosome Mapping , Chromosomes, Artificial, Yeast/genetics , Databases, Factual , Expressed Sequence Tags , Humans , RNA, Messenger/genetics , Sequence Deletion/geneticsABSTRACT
Myxoid heart disease is frequently encountered in the general population. It corresponds to an etiologically heterogeneous group of diseases, idiopathic mitral valve prolapse (IMVP) being the most common form. A rarely observed form of myxoid heart disease, X-linked myxomatous valvular dystrophy (XMVD), is inherited in an X-linked fashion and is characterized by multivalvular myxomatous degeneration; however, the histopathological features of the mitral valve do not differ significantly from the severe form of IMVP. In this article, we describe the genetic analysis of a large family in which XMVD is associated with a mild hemophilia A. The coagulation factor VIII gene position in Xq28 provided a starting point for the genetic study, which was conducted by use of polymorphic markers. Two-point linkage analysis confirmed this localization, and a maximum LOD score of 6.57 was found at straight theta=0 for two polymorphic microsatellite markers, INT-3 and DXS1008, the first one being intronic to the factor VIII gene. Haplotype analysis of this chromosomal region allowed the definition of an 8-cM minimal interval containing the gene for XMVD, between DXS8011 and Xqter.
Subject(s)
Mitral Valve Prolapse/genetics , X Chromosome , Chromosome Mapping , Female , Genetic Linkage , Hemophilia A/complications , Hemophilia A/genetics , Humans , Lod Score , Male , Mitral Valve Prolapse/complications , PedigreeABSTRACT
A putative tumor suppressor gene involved in B cell chronic lymphocytic leukemia (B-CLL) was mapped to human chromosome 13q14.3 close to the genetic markers D13S25 and D13S319. We constructed a 780-kb-long contig composed of cosmids, bacterial artificial chromosomes, and bacteriophage P1-derived artificial chromosomes that provides essential information and tools for the positional cloning of this gene. The conting contains both flanking markers as well as several additional genetic markers, three ESTs, and one potential CpG island. In addition, using one B-CLL patient, we characterized a small internal deleted region of 550 kb. Comparing this deletion with other recently published deletions narrows the minimally deleted area to less than 100 kb in our physical map. This deletion core region should contain all or part of the disrupted in B cell malignancies tumor suppressor gene.
Subject(s)
Chromosomes, Human, Pair 13 , Cosmids/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Sequence Deletion , Bacteriophages/genetics , Chromosomes, Artificial, Yeast , Chromosomes, Bacterial , Genetic Markers , Heterozygote , Humans , In Situ Hybridization, Fluorescence , Sequence Tagged SitesABSTRACT
Fluorescence in situ hybridization with a chromosome 12-specific alpha-centromeric probe and a 13q14 yeast artificial chromosome probe was performed on interphase cells from 100 patients with B-cell chronic lymphocytic leukemia. Thirty-one patients exhibited a 13q14 deletion. No correlation was found between 13q14 deletions and clinical stage, sex, or morphology. Sixteen patients had trisomy 12, including 6 (of 12) with an atypical morphology. Trisomy 12 and 13q14 abnormalities were detected concomitantly in three patients only. The analysis of patients with deletions clearly showed that in five cases a significant number of cells retained two signals with the yeast artificial chromosome probe, indicating a genetic heterogeneity among the leukemic population. Our data confirm that the 13q14 deletion is a frequent event, indicate that the concomitant occurrence of 13q14 deletion and trisomy 12 is rare but possible, and show that both abnormalities are secondary events in B-cell chronic lymphocytic leukemia.