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A Meindl

Publications and source records attributed to A Meindl.

At least 19 recordsLinked to original sources
PubMed1998

The human elk-1 gene family: the functional gene and two processed pseudogenes embedded in the IgH locus.

Elk-1 is a transcription factor whose activation by several mitogen-activated protein kinases (MAPKs) mediates the immediate early responses of the c-fos promoter to growth factors and other stimuli. Here, we report the structure of the human elk-1 gene, which we have localized about 6.5kb upstream of the properdin gene on the X chromosome. The coding sequence is interrupted by four introns; two additional introns lie within the 5' untranslated region. We have also found two elk-1-related processed pseudogenes in the human immunoglobulin heavy chain (IgH) locus, accounting for 'elk-2' previously visualized by in-situ hybridization at 14q32. A processed pseudogene evidently inserted downstream of a primordial immunoglobulin Calpha gene and was duplicated along with part of the IgH locus. Gene/pseudogene sequence comparisons and Southern blots of primate DNAs suggest that both the pseudogene insertion and the locus duplication occurred between about 30 and 60 million years ago.

Amino Acid Sequence↗
PubMed1998

Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.

X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

Antigens, CD↗
PubMed1998

An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.

The locus for the incomplete form of X-linked congenital stationary night blindness (CSNB2) maps to a 1.1-Mb region in Xp11.23 between markers DXS722 and DXS255. We identified a retina-specific calcium channel alpha1-subunit gene (CACNA1F) in this region, consisting of 48 exons encoding 1966 amino acids and showing high homology to L-type calcium channel alpha1-subunits. Mutation analysis in 13 families with CSNB2 revealed nine different mutations in 10 families, including three nonsense and one frameshift mutation. These data indicate that aberrations in a voltage-gated calcium channel, presumably causing a decrease in neurotransmitter release from photoreceptor presynaptic terminals, are a frequent cause of CSNB2.

Amino Acid Sequence↗
PubMed1998

Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course.

OBJECTIVES: To determine the utility of single-stranded conformation polymorphism (SSCP) analysis for mutation screening in the BTK (Bruton's tyrosine kinase) gene, we investigated 56 X-linked agammaglobulinemia (XLA) families. To obtain genotype/ phenotype correlations, predicted protein aberrations were correlated with the clinical course of the disease. PATIENTS: This study included 56 patients with XLA, with or without a positive family history, who were diagnosed on the basis of their clinical features, low peripheral B-cell count, and low immunoglobulin levels. Ten patients with isolated hypogammaglobulinemia and 50 healthy males served as controls. METHODS: SSCP analysis was performed for the entire BTK gene, including the exon-intron boundaries and the promoter region. Structural implications of the missense mutations were investigated by molecular modeling, and the functional consequences of some mutations also were evaluated by in vitro kinase assays and Western blot analysis. RESULTS: We report the largest series of patients with XLA to date. All but 5 of the 56 index patients with XLA screened with SSCP analysis showed BTK gene abnormalities, and in 2 of the 5 SSCP-negative patients, no BTK protein was found by Western blot analysis. There were 51 mutations, including 37 novel ones, distributed across the entire gene. This report contains the first promoter mutation as well as 14 novel missense mutations with the first ones described for the Tec homology domain and the glycine-rich motif in the SH1 domain. Each index patient had a different mutation, except for four mutations, each in two unrelated individuals. This result supports the strong tendency for private mutations in this disease. No mutations were found in the controls. CONCLUSIONS: Our results demonstrate that molecular genetic testing by SSCP analysis provides an accurate tool for the definitive diagnosis of XLA and the discrimination of borderline cases, such as certain hypogammaglobulinemia or common variable immunodeficiency patients with overlapping clinical features. Genotype/ phenotype correlations are not currently possible, making prediction of the clinical course based on molecular genetic data infeasible.

Adolescent↗
PubMed1997

BTKbase, mutation database for X-linked agammaglobulinemia (XLA)

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 368 entries from 318 unrelated families showing 228 unique molecular events. In addition to mutations the database lists also some polymorphisms and site-directed mutations. Each patient is given a unique patient identity number (PIN). Information is provided regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites forming arginine residues. These hot spots have generally pyrimidines 5'and purines 3'to the mutated cytosine. A decreased frequency of missense mutations was found in the TH, SH3 and the upper lobe of the kinase domain. The putative structural implications of all the missense mutations are given in the database showing 228 unique molecular events, including a novel missense mutation causing an R28C substitution as previously seen in the Xid mouse.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1996

Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33).

Two genes responsible for a nonspecific form of X-linked mental retardation (MRX28 and MRX33) were localized by linkage analysis with 40 highly polymorphic DNA markers situated along the entire the X chromosome. In family 1, the gene could be mapped within a 14-cM interval at Xq28, distal to the recombining marker DXS1113 (MRX28). The maximum LOD score was 2.75, with DXS52 at phi = .0. In family 2, the gene was localized within a 30-cM interval at Xp11.4-22.12 between the recombining markers DXS365 and MAOB, including the DMD gene (MRX33). Maximum LOD scores of 2.82 were obtained with markers DMD-STR49, DMD-DysII, CYBB, and DXS1068.

Child, Preschool↗
PubMed1996

Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product.

The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons contrasted with a random distribution of nonsense mutations. More than 85% of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86. No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family. An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto-architecture by interacting with actin-like filaments.

Adult↗
PubMed1996

A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3).

X-linked retinitis pigmentosa (xlRP) is a severe progressive retinal degeneration which affects about 1 in 25,000 of the population. The most common form of xlRP, RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping. Identification of microdeletions within this region has now led to the positional cloning of a gene, RPGR, that spans 60 kg of genomic DNA and is ubiquitously expressed. The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase. The C-terminal half contains a domain, rich in acidic residues, and ends in a potential isoprenylation anchorage site. The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene.

Amino Acid Sequence↗
PubMed1996

Long-range map of a 3.5-Mb region in Xp11.23-22 with a sequence-ready map from a 1.1-Mb gene-rich interval.

Most of the yeast artificial chromosomes (YACs) isolated from the Xp11.23-22 region have shown instability and chimerism and are not a reliable resource for determining physical distances. We therefore constructed a long-range pulsed-field gel electrophoresis map that encompasses approximately 3.5 Mb of genomic DNA between the loci TIMP and DXS146 including a CpG-rich region around the WASP and TFE-3 gene loci. A combined YAC-cosmid contig was constructed along the genomic map and was used for fine-mapping of 15 polymorphic microsatellites and 30 expressed sequence tags (ESTs) or sequence transcribed sites (STSs), revealing the following order: tel-(SYN-TIMP)-(DXS426-ELK1)-ZNF(CA) n-L1-DXS1367-ZNF81-ZNF21-DXS6616- (HB3-OATL1pseudogenes-DXS6950)-DXS6949-DXS694 1-DXS7464E(MG61)-GW1E(EBP)- DXS7927E(MG81)-RBM- DXS722-DXS7467E(MG21)-DXS1011E-WASP-DXS6940++ +-DXS7466E(MG44)-GF1- DXS226-DXS1126-DXS1240-HB1- DXS7469E-(DXS6665-DXS1470)-TFE3-DXS7468E-+ ++SYP-DXS1208-HB2E-DXS573-DXS1331- DXS6666-DXS1039-DXS 1426-DXS1416-DXS7647-DXS8222-DXS6850-DXS255++ +-CIC-5-DXS146-cen. A sequence-ready map was constructed for an 1100-kb gene-rich interval flanked by the markers HB3 and DXS1039, from which six novel ESTs/STSs were isolated, thus increasing the number of markers used in this interval to thirty. This precise ordering is a prerequisite for the construction of a transcription map of this region that contains numerous disease loci, including those for several forms of retinal degeneration and mental retardation. In addition, the map provides the base to delineate the corresponding syntenic region in the mouse, where the mutants scurfy and tattered are localized.

Amino Acid Sequence↗
PubMed1996

FRAXE testing.

Explore the source record for details and available documents.

Female↗
PubMed1995

Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism.

The locus for ocular albinism type 1 (OA1) has been assigned to the Xp22.3 region through both linkage and deletion mapping. The disorder was found to be genetically homogeneous, as all informative families showed convincing linkage data with markers on Xp22.3 and all identified deletions involved in the same region. The OA1 gene recently was cloned and several intragenic deletions were identified in affected individuals. We have characterized the genomic structure of the OA1 gene, which spans approximately 40 kb of genomic DNA and contains nine exons. A highly polymorphic dinucleotide repeat was identified in intron 1, that provides a useful tool for molecular diagnosis. Knowledge of the intron/exon boundaries allowed us to search for point mutations in patients' genomic DNA. All nine exons of the OA1 gene, as well as the 5' and 3' untranslated regions, were scanned for point mutations in PCR-amplified DNA from 60 OA1 patients. The mutations identified include: two frameshifts and a splice site mutation leading to truncated OA1 proteins; a deletion of a threonine codon at position 290; and four missense mutations,two of which involve amino acids located within putative transmembrane domains. Two of the mutations each occur in three apparently unrelated families, consistent with previous observations of a founder effect in OA1. Surprisingly, mutations were detected in only one-third of the patients (21 of 60) ascertained. We postulate that mutations not yet identified in either regulatory elements of the OA1 gene, or in other gene(s) located within the same chromosomal region, may be common cause of X-linked ocular albinism.

Albinism, Ocular↗
PubMed1995

A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa.

X-linked retinitis pigmentosa (XLRP) is characterized by retinal degeneration with night blindness and progressive reduction of the visual fields. By linkage and deletion analysis a gene locus (RP3) has been mapped to the short arm of the X chromosome between the genes CYBB and OTC. Analysis of transcript in this region has revealed a gene which is abundantly expressed in human retina and encodes a putative membrane protein with significant homologies to short consensus repeat (SCR/sushi) domains known from selections and complement proteins. The gene termed SRPX (sushi-repeat-containing protein, x chromosome) is deleted in an RP patient who also suffers from chronic granulomatous disease and McLeod syndrome. A 75 kb deletion removing exon 1 of the gene was also found in two brothers of a second XLRP family. However, no further functionally significant mutations were detected by SSCP screening of all 10 exons in 34 unrelated XLRP patients nor by full length RT-PCR sequencing in two RP3 families. The role of this highly conserved retinal gene in the pathogenesis of RP therefore remains to be determined.

Adult↗
PubMed1995

A PCR based X-chromosome inactivation assay for carrier detection in X-linked immunodeficiencies using differential methylation of the androgen receptor gene.

Carrier detection in X-linked immunodeficiencies (X-SCID, WAS, XLA) relies on the demonstration of non-random X inactivation patterns in blood cell lineages. Only a limited number of cells are available after cell separation methods. PCR-based techniques are therefore necessary to analyze active and inactive X chromosomes. Amplifying a polymorphic CAG repeat in the first exon of the androgen receptor gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme allows to distinguish between the paternal and maternal alleles and to identify their methylation status. DNA from B-, T-lymphocytes and total peripheral leukocytes of normal males, females and obligate carriers of X-linked immunodeficiencies were analyzed. The results of this PCR-based X inactivation assay are concordant with the standard methylation studies at the DXS255 locus using Southern blotting. This PCR assay provides a rapid and informative (heterozygosity > 90%) method in carrier detection of X-linked immunodeficiencies and other X-linked disorders, which show non-random X inactivation in cell lineages from the affected tissues.

DNA↗
PubMed1994

Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

Adrenal hypoplasia congenita (AHC) is an X-linked disorder characterized by primary adrenal insufficiency. Hypogonadotropic hypogonadism (HHG) is frequently associated with this disorder but is thought not to be caused by the low adrenal androgen levels due to adrenal hypoplasia. It is uncertain whether there are two distinct yet physically linked genes responsible for AHC and HHG or a single gene responsible for both diseases. AHC can occur as a part of a contiguous deletion syndrome together with Duchenne muscular dystrophy (DMD) and/or glycerol kinase deficiency (GKD). From the analysis of deletions, the following gene order has been deduced: Xpter-AHC-GKD-DMD-cen. An AHC critical region of 200-500 kilobases has been defined by physical mapping and partially overlaps with a 160-kilobase dosage-sensitive sex (DSS) reversal critical region. The DAX-1 (DSS-AHC critical region on the X, gene 1) gene was isolated and found to encode a new member of the nuclear hormone receptor family. Here we report that DAX-1 is deleted in 14 patients and point mutations were found in the coding region in DNA from 12 unrelated individuals. All AHC patients over 14 years old and with only point mutations in DAX-1 were also diagnosed with HHG, confirming that the DAX-1 gene is responsible for both X-linked AHC and HHG. But in four sporadic cases and a single familial case, no point mutations were found, suggesting genetic heterogeneity or differential expression of DAX-1.

Adrenal Insufficiency↗
PubMed1994

A patient with an interstitial deletion in Xp22.3 locates the gene for X-linked recessive chondrodysplasia punctata to within a one megabase interval.

A male patient carrying an interstitial deletion in Xp22.3 and affected by Kallmann syndrome, X-linked ichthyosis and mental retardation, but without chondrodysplasia punctata or short stature, was investigated with molecular probes from the distal Xp22.3 region. By means of a novel probe, M115, from the relevant region, the distal deletion breakpoint was shown to be between 3.18 and 3.57 Mb from Xptel. As the patient is not affected by X-linked recessive chondrodysplasia punctata, the gene for this disease can therefore be located to within an interval of less than one megabase proximal to the pseudoautosomal boundary. If the chondrodysplasia punctata gene is associated with a CpG island, this leaves only two islands at 2760 and 3180 kb from the Xp telomere as the most promising candidate sites for this gene.

Chondrodysplasia Punctata↗