Genotype-phenotype correlation in three homozygotes for the cystic fibrosis mutation 2183AA-->G shows a severe phenotype.
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Cystic Fibrosis↗
Biomedical subjects
X Estivill
Publications and source records attributed to X Estivill.
Hereditary neuropathy with liability to pressure palsies: two cases with a reciprocal translocation t(16;17)(q12;11.2) interrupting the PMP22 gene.
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Chromosomes, Human, Pair 16↗
Cloning and characterization of human FTCD on 21q22.3, a candidate gene for glutamate formiminotransferase deficiency.
We have identified a new human gene, FTCD, which maps to chromosome 21q22.3 and encodes the enzyme formiminotransferase cyclodeaminase, an intermediate metabolism enzyme that links histidine catabolism to folate metabolism. The major cDNA encodes a protein containing 541 amino acid residues and shows 84% identity with porcine FTCD. Several other cDNAs have been isolated, which may result from alternative splicing events and have the potential to code for three different protein isoforms. The gene is highly expressed in human fetal and adult liver. The two FTCD protein domains show high sequence similarity to two distinct open reading frames from eubacterial genomes, suggesting that eukaryotic FTCD appeared through a gene fusion event. Defects in the glutamate formiminotransferase pathway have been documented, and the deficiency is presumed to be inherited as an autosomal recessive trait. The sequence reported here may be helpful in identifying the primary defect in glutamate formiminotransferase deficiency and establishing a molecular diagnosis.
Alternative Splicing↗
HMG20A and HMG20B map to human chromosomes 15q24 and 19p13.3 and constitute a distinct class of HMG-box genes with ubiquitous expression.
The HMG box encodes a conserved DNA binding domain found in many proteins and is involved in the regulation of transcription and chromatin conformation. We describe HMG20A and HMG20B, two novel human HMG box-containing genes, discovered within the EURO-IMAGE Consortium full-length cDNA sequencing initiative. The predicted proteins encoded by these two genes are 48.4% identical (73.9% within the HMG domain). The HMG domain of both HMG20 proteins is most similar to that of yeast NHP6A (38% to 42%). Outside of this domain, HMG20 proteins lack any significant homology to other known proteins. We determined the genomic structure and expression pattern of HMG20A and HMG20B. Both genes have several alternative transcripts, expressed almost ubiquitously. HMG20A maps to chromosome 15q24 (near D15S1227) and HMG20B to 19p13.3 (between D19S209 and D19S216). The HMG20 genes define a distinct class of mammalian HMG box genes.
Alternative Splicing↗
Identification and expression analysis of C15orf3, a novel gene on chromosome 15q21.1-->q21.2.
We have isolated C15orf3, a novel human gene that lacks homology to any known gene family. The C15orf3 gene encodes a transcript of 1676 nt with an ORF of 187 amino acids and a predicted protein product size of 20.8 kDa. Northern blot analysis showed ubiquitous expression in adult tissues. EST database searching revealed the presence of C15orf3 homologs in rat and mouse. C15orf3 was mapped to chromosome 15q21.1-->q21.2 using the Stanford G3 radiation hybrid panel.
Adenovirus E1A Proteins↗
Cloning, mapping and expression analysis of VPS33B, the human orthologue of rat Vps33b.
We have identified VPS33B, the human ortholog of rat Vps33b. VPS33B encodes a transcript of 2482 nt with an ORF of 617 amino acids and a predicted protein size of 70.6 kDa. VPS33B contains a Sec-1 domain shared with a family of proteins involved in protein sorting and vesicular trafficking. Enriched expression of VPS33B was observed in testis. VPS33B was positioned at chromosome 15q26.1 by radiation hybrid mapping.
Amino Acid Sequence↗
A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase.
Down syndrome individuals develop abnormalities of most organs, including all the pathological and neurochemical features of Alzheimer's disease, by the early age of 30 yr. Here, we report the isolation and characterization of BACE2, a gene mapping on human chromosome 21q22.3, which is highly similar to a transmembrane aspartyl protease, BACE (for beta-site APP-cleaving enzyme), which is able to catalyze the beta-secretase cleavage of Alzheimer's amyloid precursor protein (APP). BACE2 is expressed in a wide variety of organs and tissues, with several transcripts due to alternative splicing and the use of two polyadenylation signals. The BACE2 gene product is a 518 amino acid protein with the signature of an aspartic protease, a 20-residue signal peptide, and two putative N-glycosylation sites. In addition, and similarly to BACE, BACE2 differs from the other members of the human aspartic protease family in the number and distribution of putative disulfide bonds and in the presence of an extended C-terminal region which contains a predicted transmembrane segment. BACE2 could be involved in the Alzheimer-like neuropathology of Down syndrome, as well as in Alzheimer's disease linked to chromosome 21 but not showing mutations in APP.
Alternative Splicing↗
Cloning of the novel gene TM6SF1 reveals conservation of clusters of paralogous genes between human chromosomes 15q24-->q26 and 19p13.3-->p12.
As the result of the EUROIMAGE Consortium sequencing project, we have isolated and characterized a novel gene on chromosome 15, TM6SF1. It encodes a 370 amino acid product with enhanced expression in spleen, testis and peripheral blood leukocytes. We have identified another gene, paralogous to TM6SF1 on chromosome 19p12, TM6SF2, with an overall similarity of 68% and 52% identity at the protein level. This conservation has led us to uncover a series of eleven genes in 19p13.3-->p12 with close homology to genes in 15q24--> q26. The percentage of sequence similarity between each paralogous pair of genes at the protein level ranges between 43 and 89%. A partial conservation of synteny with mouse chromosomes 7, 8 and 9 is also observed. The corresponding orthologous genes in mouse of human TM6SF1 and TM6SF2 show a high degree of amino acid sequence conservation.
Amino Acid Sequence↗
Association study of the chromosomal region containing the FCER2 gene suggests it has a regulatory role in atopic disorders.
On the basis of studies with animal models, the gene for the low-affinity receptor for immunoglobulin E (IgE) (FCER2, CD23) has been implicated as a candidate for IgE-mediated allergic diseases and bronchial hyperreactivity, or related traits. Given evidence for genetic complexity in atopic disorders, we sought to study two European subpopulations, Finnish and Catalonian. We studied three phenotypic markers: (1) total serum IgE level; (2) asthma; and (3) specific IgE level for a mixture of the most common aeroallergens in Finland. Altogether, eight polymorphic markers spanning a region of 10 cM around the FCER2 gene on chromosome 19p13 were analyzed in 124 families. The physical order of the markers and the location of the FCER2 gene were confirmed by using radiation hybrids. The allele and haplotype association study showed a suggestive haplotype association (significance of p </= 0.03 based on a permutation test) for a high serum IgE response. In a subset of chromosomes segregating with asthma in families with two or more affected members, a single haplotype was found to be highly enriched (p = 8.3 x 10(-6)). However, sequence polymorphisms, which would verify structural differences in the FCER2 gene, were not detected in the coding region of the receptor. Our results suggest that chromosome 19p13 might harbor a genetic determinant of IgE-related traits. Studies in other population samples are needed to verify this finding.
Adult↗
Identification and expression analysis of C3orf1, a novel human gene homologous to the Drosophila RP140-upstream gene.
We have isolated C3orf1, a novel gene on human chromosome 3 showing homology to the Drosophila RP140-upstream gene. When mutated, RP140-upstream causes lethality in flies through an unknown mechanism, perhaps by interfering with transcription of the RP140 RNA polymerase subunit. The human C3orf1 gene encodes a predicted membrane protein of 32.2 kDa with four transmembrane domains without any other known motifs. Northern blot analysis showed generalized expression of C3orf1, enhanced in heart and skeletal muscle. EST database searching revealed the existence of a homologue gene in mouse. Thus, the C3orf1 gene is conserved and may perform an essential function in all tissues in mammals.
Amino Acid Sequence↗
Homozygosity for the protein S Heerlen allele is associated with type I PS deficiency in a thrombophilic pedigree with multiple risk factors.
The multifactorial character of thrombotic disease is shown in a Spanish pedigree in which the propositus, with recurrent deep vein thrombosis, inherited the factor V R/Q506 mutation, the prothrombin 20210G/A variant and type III Protein S deficiency. Among 14 relatives carrying one or two of these three risk factors, thrombosis is present in a heterozygote for R/Q506 and in another for 20210G/A, who also had slightly positive antiphospholipid antibodies. Type I PS deficiency was also found in a young asymptomatic woman. PROS1 analysis showed coexistence of type III and type I PS deficiency to be associated with heterozygosity and homozygosity, respectively, for the P460 or PS Heerlen allele of the S/P460 variant. Analysis of PS values in this and other pedigrees segregating this variant revealed that not only free but also mean total PS levels are slightly but significantly lower in the SP460 heterozygotes than in the SS460 homozygotes. These findings strongly suggest a role of the P460 variant in the expression of the PS deficient phenotype.
Adult↗
Large deletions of chromosome 9p in cutaneous malignant melanoma identify patients with a high risk of developing metastases. Hospital Clinic Malignant Melanoma Group, University of Barcelona.
Cutaneous malignant melanoma (CMM) is an aggressive tumour with a high metastatic potential. Deletions of chromosome 9p have been detected in CMM, some of which involve the CDKN2A/p14ARF genes. Loss of heterozygosity (LOH) of 16 microsatellite markers on 9p and mutations in the CDKN2A/p14ARF genes had been previously studied in 32 melanoma patients by our group. 9p deletions were detected in 15 primary tumours (45.5%) and are here correlated with the clinical outcome over 5 years and compared with classical prognostic factors. Eight of the 32 patients developed metastases (25%). The metastases were all detected within 768 days of the initial diagnosis. The patients without metastases were last monitored at least 1621 days after diagnosis. None of the 21 patients with more than eight microsatellites conserved developed metastases, whereas all of the eight patients who developed metastases had eight or more markers deleted. The sensitivity of this analysis to predict metastases was 100% (specificity 84%), whereas the sensitivity for the same sample using a Breslow thickness > 3 mm was 62.5% (specificity 68%). LOH of eight or more of the 9p microsatellite markers is therefore a useful prognostic factor to predict the development of metastases in the first 4.4-6.3 years (1621-2294 days).
Chromosome Deletion↗
Cloning of the human phospholipase A2 activating protein (hPLAP) gene on the chromosome 9p21 melanoma deleted region.
Cutaneous malignant melanoma (CMM) is a common skin cancer. About 50% of CMM sporadic tumours have lost one copy of the chromosome 9p21 region. To identify genes involved in the initiation and/or progression of CMM we have characterised the 9p21 melanoma deleted region and screened the human expressed sequence tag (EST) databases (dbEST) to search for expressed genes. We have identified the gene that encodes the human orthologue of the rat phospholipase A2 activating protein (PLAP). PLAP was considered a potential candidate to be involved in malignant melanoma because it maps to the critical region for CMM and because the PLA2 gene has been identified as a modifier of the APC gene, responsible for the adenomatous polyposis phenotype in the mouse. PLAP encodes a protein of 738 amino acids and has a high DNA (90%) and protein (97%) sequence similarity with the rat and mouse PLAP protein. PLAP has a region of WD40 repeats in the amino-terminus, which allows us to include this protein in the superfamily of beta-transducin proteins. Northern blot hybridisation gave a fragment of 4.5 kb, with higher expression in heart compared to other tissues. PLAP was localised at chromosome 9p21, between marker AFM218xg11 and TEK. SSCP analysis of the coding region of PLAP revealed no variants in the studied samples, but one of six CMM samples analysed by RT-PCR showed specific inactivation of PLAP. Despite PLAP's important role in mediating several cellular responses and its localisation to the chromosome 9p21 region deleted in CMM, it is unlikely that point mutations or deletions in the coding region of PLAP are responsible for the initiation or progression of CMM. Further studies on PLAP inactivation should be performed to clarify its potential involvement in CMM.
Amino Acid Sequence↗
Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1.
Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes have been described. The gene responsible for type I, SLC3A1, encodes the amino acid transporter rBAT. This gene is not responsible for types II or III. Recently the type III locus (CSNU3) was mapped by two groups to overlapping 6-Mb regions on chromosome 19q. In the present study, we restrict the critical region for non-type I cystinuria to 2.4 Mb by recombination analysis in Italian, German, and Spanish families. For this purpose, we have used the microsatellite markers described in the region plus new microsatellites that we have developed. Our results locate the non-type I cystinuria gene in an interval flanked by the markers C13 and D19S587, which are about 2.8 cM apart.
Chromosome Mapping↗
[Clinical characterization, molecular and FISH studies in 80 patients with clinical suspicion of Williams-Beuren syndrome].
BACKGROUND: Williams-Beuren syndrome is a developmental disorder affecting vascular and connective tissues and central nervous system. The syndrome is caused by a submicroscopic deletion in the chromosome 7 implicating the 7q11.23 region. Fluorescence in situ hybridization (FISH) and molecular studies allow us to confirm the clinical suspicion of this syndrome. PATIENTS AND METHODS: We report clinical evaluation, FISH using Elastin Williams/D7S427 probe and molecular study with markers: D7S672, D7S653, D7S489B, D7S2476, D7S1870 and D7S489A, in 80 patients referred to test for Williams-Beuren syndrome. RESULTS: We found hemizygosity for the critical region in 36 patients. From 69 cases studied by FISH, 28 showed the deletion. Molecular studies in 78 cases showed loss of heterozygosity (LOH) in 26 patients. The patients presented the deletion from the paternal or maternal chromosome at equal frequency. Clinical evaluation of mental retardation, facial features, esotopia dental, malocclusion, hoarse voice, supravalvular aortic stenosis (SVAS), hernias, join limitation, WBS personality and mental retardation from positive and negative patients showed estatistical significant differences for all items except mental retardation and joint limitation. The most significant item was the presence of SVAS. CONCLUSION: This study confirms the usefulness of genetic studies as a diagnostic tool for William-Beuren Syndrome.
Chromosome Aberrations↗
Single-strand conformation polymorphism analysis in the FMR1 gene.
The fragile X syndrome is due to an expansion of the CGG trinucleotide repeat in the FMR1 gene and hypermethylation of its 5' upstream CpG island in about 95% of the cases. The remaining 5% of cases correspond to other molecular alterations in FMR1 gene such as partial or complete deletions, or point mutations within the coding sequence. We selected 31 patients with clinical manifestations of fragile X syndrome, scoring 16 or more in Hagerman's checklist, but without the CGG expansion. We performed single-strand conformation polymorphism analysis using a nonradioactive technique (silver staining) and we detected six anomalous migrations that, by sequence analysis, corresponded to six nucleotide changes. We screened two different populations (control and fragile X) for these changes, and concluded that they correspond to five new polymorphisms within the FMR1 gene and to one possible synonymous mutation.
Fragile X Messenger Ribonucleoprotein 1↗
Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome.
The human homologue (MNBH/DYRK1) of the Drosophila minibrain gene maps to human chromosome 21 within the Down syndrome (DS) critical region and is within the region minimally deleted in chromosome 21-linked microcephaly. As a first step in gaining insight into the role that MNBH may have in human neurogenesis, and as a lead-up to the development of mouse models for MNBH overexpression, we have characterized the gene at the molecular level. We describe here the MNBH full-length transcript, alternative splicing, expression profile, and genomic organization. The full-length cDNA of MNBH is 5. 2 kb and is composed of 17 exons spanning 150 kb, between markers D21S335 and D21S337. Transcripts MNBHa and MNBHb arise from the use of different first exons in the 5'-UTR and are differentially expressed. MNBHa is expressed ubiquitiously in a broad spectrum of tissues and is apparently under the control of a CpG island. MNBHb is expressed only in heart and skeletal muscle and is apparently under the control of a TATA-like box. Four alternative splicing events affecting the C-terminus of the protein yield at least four isoforms of MNBH (MNBH-iso1, MNBH-iso2, MNBH-iso3, and MNBH-iso4). A PEST sequence, potentially involved in the rapid degradation of the protein, is present in all the isoforms. A histidine repeat and a serine/threonine domain are present only in the largest form of the protein (MNBH-iso1). MNBH was overexpressed 1.5-fold in DS brains and Dyrk1 about 2.1-fold in the brains of the Ts65Dn mice. The information provided here should be valuable for MNBH mutation studies and aid in the development of DS animal models.
3' Untranslated Regions↗
Cloning, expression and chromosomal localization of a human testis 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene.
6-Phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2/FBPase-2) is a bifunctional enzyme responsible for the synthesis and breakdown of Fru-2,6-P2, a key metabolite in the regulation of glycolysis. Several genes encode distinct PFK-2/FBPase-2 isozymes that differ in their tissue distribution and enzyme regulation. In this paper, we present the isolation of a cDNA from a human testis cDNA library that encodes a PFK-2/FBPase-2 isozyme. Sequencing data show an open reading frame of 1407 nucleotides that codifies for a protein of 469 amino acids. This has a calculated molecular weight of 54kDa and 97% similarity with rat testis PFK-2/FBPase-2, with complete conservation of the amino acid residues involved in the catalytic mechanism. Fluorescence in-situ hybridization (FISH) localized testis PFK-2/FBPase-2 gene (PFKFB4) in human chromosome 3 at bands p21-p22. A Northern blot analysis of different rat tissues showed the presence of a 2.4-kb mRNA expressed specifically in testis. In mammalian COS-1 cells, the human testis cDNA drives expression of an isozyme with a molecular weight of 55kDa. This isozyme shows clear PFK-2 activity. Taken together, these results provide evidence for a new PFK-2/FBPase-2 gene coding for a human testis isozyme.
Amino Acid Sequence↗