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Biomedical subjects

U Francke

Publications and source records attributed to U Francke.

At least 37 records · Page 2Linked to original sources
PubMed1999

The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q.

Neuregulin-2 (NRG2) is a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ErbB family of receptors, neuregulin-2 induces the growth and differentiation of epithelial, neuronal, glial and other types of cells. In this study, we have cloned the human neuregulin-2 gene, and determined its genomic structure and alternative splicing patterns. By using radiation hybrid mapping panels, the human NRG2 gene was mapped to the D5S658-D5S402 region within 5q23-q33, close to an autosomal recessive form of demyelinating Charcot-Marie-Tooth (CMT) disease. The NRG2 gene was found to be on two yeast artificial chromosomes overlapping the candidate interval and was, thus, considered a good positional candidate for this form of CMT. When the entire neuregulin-2 coding sequence and splice junctions were explored, however, no mutation was identified in one CMT family linked to 5q23-q33. In addition, three intronic single nucleotide polymorphisms were identified in the NRG2 gene. Genotyping in two families localized the NRG2 gene outside of the revised candidate interval between D5S402-D5S210 and excluded NRG2 as the gene responsible for this form of CMT disease.

Adult↗
PubMed1999

Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.

Amino Acid Sequence↗
PubMed1999

Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes.

Fibrillin-1 (FBN1) contains 47 epidermal growth factor (EGF)-like domains characterized by six conserved cysteine residues. Cysteine substitutions that disrupt one of the three disulfide bonds are frequent causes of Marfan syndrome (MFS). We identified 19 new substitutions involving cysteine residues in each of the six positions of EGF-like domains. Allele-specific mRNA assays revealed equal abundance of mutant and normal FBN1 transcripts in all 10 individuals studied. Quantitative pulse-chase analysis of fibrillin protein was performed on 25 mutant fibroblast strains with substitutions of 22 different cysteine residues in 18 different EGF-like domains spanning the entire gene. Normal synthesis and stability of mutant fibrillin molecules was seen in 20/25 individuals, 11 of whom showed delayed intracellular processing and/or secretion. In the remaining five cases, the mutant protein was apparently unstable. In four of these five cases, the second or third disulfide bond of EGF-like domains immediately preceding an 8-cysteine or hybrid domain was affected. All but two mutations caused severe reduction of matrix deposition, which was attributed to a dominant-negative effect of mutant molecules. For genotype/phenotype comparisons, clinical data on 25 probands and 19 mutation-positive family members were analyzed. Ocular manifestations were among the most consistent features (ectopia lentis in 86%, myopia in 80%). Nine mutations encoded by exons 26-32 resulted in early-onset classic MFS and, in one case, neonatal-lethal MFS. Mutations outside this region were associated with variable clinical phenotypes, including individuals with fibrillinopathies not meeting diagnostic criteria for MFS.

Adolescent↗
PubMed1999

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Alleles↗
PubMed1999

Williams-Beuren syndrome: genes and mechanisms.

Williams-Beuren syndrome (WBS; OMIM 194050) is caused by heterozygous deletions of approximately 1.6 Mb of chromosomal sub-band 7q11.23. The deletions are rather uniform in size as they arise spontaneously by inter- or intrachromosomal crossover events within misaligned duplicated regions of high sequence identity that flank the typical deletion. This review will discuss the status of the molecular characterization of the deletion and flanking regions, the genes identified in the deletion region and their possible roles in generating the complex multi-system clinical phenotype.

Chromosome Deletion↗
PubMed1999

In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit.

Human chromosome region 15q11-q13 contains a cluster of oppositely imprinted genes. Loss of the paternal or the maternal alleles by deletion of the region or by uniparental disomy 15 results in Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Hence, the two phenotypically distinct neurodevelopmental disorders are caused by the lack of products of imprinted genes. Subsets of PWS and AS patients exhibit 'imprinting mutations', such as small microdeletions within the 5' region of the small nuclear ribonucleoprotein polypeptide N ( SNRPN ) transcription unit which affect the transcriptional activity and methylation status of distant imprinted genes throughout 15q11-q13 in cis. To elucidate the mechanism of these long-range effects, we have analyzed the chromatin structure of the 150 kb SNRPN transcription unit for DNase I- and Msp I-hypersensitive sites. By using an in vivo approach on lymphoblastoid cell lines from PWS and AS individuals, we discovered that the SNRPN exon 1 is flanked by prominent hypersensitive sites on the paternal allele, but is completely inaccessible to nucleases on the maternal allele. In contrast, we identified several regions of increased nuclease hypersensitivity on the maternal allele, one of which coincides with the AS minimal microdeletion region and another lies in intron 1 immediately downstream of the paternal-specific hypersensitive sites. At several sites, parental origin-specific nuclease hypersensitivity was found to be correlated with hypermethylation on the allele contributed by the other parent. The differential parental origin-dependent chromatin conformations might govern access of regulatory protein complexes and/or RNAs which could mediate interaction of the region with other genes.

Alleles↗
PubMed1999

TBL2, a novel transducin family member in the WBS deletion: characterization of the complete sequence, genomic structure, transcriptional variants and the mouse ortholog.

Williams-Beuren syndrome (WBS) is a developmental disorder with multi-system manifestations caused by haploinsufficiency for contiguous genes deleted in chromosome region 7q11.23. The size of the deletion is similar in most patients due to a genomic duplication that predisposes to unequal meiotic crossover events. While hemizygosity at the elastin locus is responsible for the cardiovascular features, the contribution of other genes to the WBS phenotype remains to be demonstrated. We have identified a novel gene, TBL2, in the common WBS deletion. TBL2 is expressed as a 2. 4-kb transcript predominantly in testis, skeletal muscle, heart and some endocrine tissues, with a larger approximately 5-kb transcript detected ubiquitously at lower levels. TBL2 encodes a protein with four putative WD40-repeats. An alternatively spliced transcript in TBL2 introduces a novel second exon with an in frame stop codon. This mRNA encodes a 75 amino acid protein with 43 amino acids identical to TBL2 at the N-terminus and no known functional domain. The mouse homolog, Tbl2, shows 84% sequence identity at the nucleotide level and 92% similarity at the amino acid level. Comparison of the mouse and human sequences identifies a conserved region that extends upstream of the previously published sequence with an initiation codon common to both species that adds 21 amino acids at the N-terminus. The Tbl2 gene has been mapped to mouse chromosome 5 in a region of conserved synteny with human 7q11.23. Since haploinsufficiency has been shown for other WD-repeat containing proteins, hemizygosity of TBL2 may contribute to some of the aspects of the complex WBS phenotype.

Amino Acid Sequence↗
PubMed1999

Identification of GTF2IRD1, a putative transcription factor within the Williams-Beuren syndrome deletion at 7q11.23.

Williams-Beuren syndrome (WBS) is a microdeletion syndrome caused by haploinsufficiency of genes at 7q11.23. Here we describe the identification and characterization of a novel gene named GTF2IRD1, for GTF2I-repeat domain 1, within the WBS deletion region. Northern blot analysis revealed ubiquitous expression during development with two transcripts of 3.6 kb and 5.0 kb generated by alternative splicing. GTF2IRD1 encodes a protein of 944 amino acids that contains a region of high similarity to a unique motif with helix-loop-helix forming potential occurring within the transcription factor GTF2I. Analogous to TFII-I, the product of GTF2IRD1 may have the ability to interact with other HLH-proteins and function as a transcription factor or as a negative transcriptional regulator. A recent report of the identification of a muscle-specific transcription factor, MusTRD1, supports this hypothesis (O'Mahoney et al., 1998). The open reading frame described for MusTRD1 is identical to that of GTF2IRD1; however, the putative MusTRD1-protein is 486 amino acids shorter than the predicted protein encoded by GTF2IRD1. A heterozygous deletion of GTF2IRD1 may contribute to the complex WBS phenotype.

Amino Acid Sequence↗
PubMed1998

Conserved chromosomal location and genomic structure of human and mouse fatty-acid amide hydrolase genes and evaluation of clasper as a candidate neurological mutation.

Fatty-acid amide hydrolase (FAAH) is a membrane-bound enzyme that degrades neuromodulatory fatty acid amides, such as oleamide and anandamide, and is expressed in the mammalian central nervous system. To evaluate FAAH genes as candidates for neurogenetic diseases in humans and mice, we have mapped the loci in both species and have determined their intron-exon structures. The human FAAH gene was mapped to region 1p34-p35, closely linked to D1S197 and D1S443, by using PCR analysis of somatic cell hybrid (SCH) and radiation hybrid mapping panels. Analysis of an SCH mapping panel and a mouse interspecific backcross panel has localized the Faah gene to the conserved syntenic region on mouse chromosome 4, close to the neurological mutation clasper. Faah gene rearrangements were excluded by Southern blot analysis of clasper DNA. No sequence abnormality was detected in PCR products containing the 15 exons and splice junctions of the mouse Faah gene. FAAH protein levels were normal in clasper mouse tissues as determined by enzyme activity assays and Western blotting.

Amidohydrolases↗
PubMed1998

Genes for the CPE receptor (CPETR1) and the human homolog of RVP1 (CPETR2) are localized within the Williams-Beuren syndrome deletion.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting multiple systems. Haploinsufficiency of genes deleted in chromosomal region 7q11.23 is the likely cause for this syndrome. We now report the localization of the genes for the CPE-R (Clostridium perfringens enterotoxin receptor, CPETR1) and the human homolog of RVP1 (rat ventral prostate 1 protein, CPETR2), both previously mapped to 7q11, to the WBS critical region. A single nucleotide polymorphism (SNP) present in CPETR1 has been identified and was used to determine parental origin of the deleted allele in five informative families. The mouse homologs Cpetr1 and Cpetr2 were identified and mapped to the conserved syntenic region on mouse chromosome 5. Northern blot analysis of CPETR1 demonstrates tissue specificity, with expression in kidney, lung, thyroid, and gastrointestinal tissues. In mouse, Cpetr1 is expressed in the early embryo, appears to be developmentally upregulated during gestation, and is present in adult tissues. Our results suggest a role for CPE-R in internal organ development and function during pre- and postnatal life.

5' Untranslated Regions↗
PubMed1998

Five SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome.

The SWI/SNF-related, matrix-associated, actin-dependent regulators of chromatin (SMARC), also called BRG1-associated factors, are components of human SWI/SNF-like chromatin-remodeling protein complexes. We mapped five human SMARC genes toregions on four different human chromosomes, SMARCC1 to 3p23-p21, SMARCC2 to 12q13-q14, SMARCD1 to 12q13-q14, SMARCD2 to 17q23-q24, and SMARCD3 to 7q35-q36. SMARCC1, SMARCC2, and SMARCD1 are assigned to chromosomal regions that are frequently involved in somatic rearrangements in human cancers. SMARCD1 was mapped to the critical region of Allgrove syndrome; however, no mutation was identified in one Allgrove syndrome family studied.

Abnormalities, Multiple↗
PubMed1998

Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome.

The gene for the gastrin-releasing peptide receptor (GRPR) has been mapped to a candidate region for Rett syndrome (RTT) on the short arm of the X chromosome. The recent report of a translocation that disrupted the gene in an individual with mental retardation and autistic behavior prompted us to examine GRPR as a possible locus for RTT. Genomic polymerase chain reaction amplification of exons followed by single-strand conformation analysis screening in 25 unrelated RTT-affected individuals and by direct sequencing in 12 others has failed to detect any mutation. No gross structural rearrangements were found by Southern analysis of DNA from six unrelated RTT-affected individuals. A high-frequency biallelic polymorphism caused by two single nucleotide substitutions in exon 2 was discovered. The allele frequencies were identical in the RTT population as compared to 100 normal control X chromosomes. This polymorphism will enable future evaluation of the GRPR locus as a candidate for other X-linked mental retardation or neurobehavioral syndromes.

Blotting, Southern↗
PubMed1998

Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1).

The most likely cause of the Rett syndrome (RTT) is an X-linked dominant mutation lethal in hemizygous males. Previous exclusion mapping studies have identified putative regions for the RTT gene on the X chromosome. In the present study, we evaluated two candidate genes, glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1/XAP-4), chosen because of their expression patterns and functions in the central nervous system and their location in the nonexcluded region of Xq. The intronless gene GLUD2, located in Xq25 and expressed in neuronal and testicular tissues, is involved in the metabolism of glutamate, a neurotransmitter reported to be elevated in the spinal fluid of RTT individuals. The GLUD2 gene was screened for mutations by Southern hybridization and by direct sequencing of polymerase chain reaction (PCR) products. The GDI1 gene in Xq28, also known as RABGDIA or XAP-4, encodes a human GDI that is expressed predominantly in neuronal and sensory tissues. All 11 exons and splice junctions of the GDI1 gene were PCR-amplified and sequenced directly or screened by single-strand conformation analysis. No mutation in either of these two genes was found in 22 RTT patients. Therefore, GLUD2 and GDI1 can be excluded as candidate genes for this syndrome.

Blotting, Southern↗
PubMed1998

Structure of the human paralemmin gene (PALM), mapping to human chromosome 19p13.3 and mouse chromosome 10, and exclusion of coding mutations in grizzled, mocha, jittery, and hesitant mice.

Paralemmin is a newly identified protein that is associated with the plasma membrane and with intracellular membranes through a lipid anchor. It is abundant in brain, is expressed at intermediate levels in the kidney and in endocrine cells, and occurs at low levels in many other tissues. As it is a candidate for genetic disorders that affect membrane functions, we have determined the structure of the human paralemmin gene, PALM, showing that it is organized into nine exons. Moreover, we have performed chromosomal assignments of the human and mouse paralemmin genes, localizing them to regions of homology at human 19p13.3 and the central mouse chromosome 10. Finally, mutation analysis using RNA from mice homozygous for the mutant genes grizzled (gr), mocha (mh), mocha 2J (mh2J), jittery (ji) and hesitant (ji(hes)), which map to this area, excluded mutations in their Palm coding sequences.

Amino Acid Sequence↗
PubMed1998

A mouse single-copy gene, Gtf2i, the homolog of human GTF2I, that is duplicated in the Williams-Beuren syndrome deletion region.

We have cloned and characterized Gtf2i, the mouse homolog of human GTF2I (general transcription factor II-I), which encodes BAP-135, a target for Bruton's tyrosine kinase. GTF2I represents the telomeric and functional copy of a duplicated gene flanking the 2-Mb Williams-Beuren syndrome (WBS) common deletion at 7q11.23. GTF2I is deleted in WBS, while a truncated centromeric pseudogene (GTF2IP1) is not deleted. In mouse, there appears to be only a single locus, Gtf2i, which we mapped to mouse chromosome 5 in a region of conserved mouse-human synteny. Gtf2i is 87.7% identical to GTF2I at the nucleotide and 97% at the amino acid level and generates several alternatively spliced transcripts. The gene is widely expressed in adult tissues and equally in all areas of the brain. Gtf2i transcript is detectable in ES cells by RT-PCR and on Northern blots of tissues from 7-dpc embryos. A ubiquitous expression pattern is seen by Northern and tissue in situ hybridization studies of 14-dpc embryos.

Alternative Splicing↗
PubMed1998

Marfan Database (third edition): new mutations and new routines for the software.

The Marfan database is a software that contains routines for the analysis of mutations identified in the FBN1 gene that encodes fibrillin-1. Mutations in this gene are associated not only with Marfan syndrome but also with a spectrum of overlapping disorders. The third version of the Marfan database contains 137 entries. The software has been modified to accommodate four new routines and is now accessible on the World Wide Web at http://www.umd.necker.fr

Computer Communication Networks↗