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1.
ES2 is a gene deleted in DiGeorge syndrome (DGS) and velocardiofacial
syndrome (VCFS) which has homologs in species as distant as Caenorhabditis
elegans and Drosophila . The function of ES2 is unknown, and the predicted
protein sequence does not contain motifs which suggest a particular role in
the developmental defects present in DGS and VCFS. Here we show that the
mouse homolog, Es2 , is transcribed in two forms resulting from the use of
alternative polyadenylation signals. Structural analysis programs predict
that the Es2 -encoded peptide has a coiled-coil domain, and transfection
experiments with an Es2 -green fluorescent protein (GFP) fusion construct
show that the peptide is recruited into the nucleus. Es2 is highly
expressed during mouse embryogenesis from E7 onwards. In situ hybridization
with an RNA probe revealed that the gene is widely expressed; however,
relatively higher expression was detected in the nervous system, with a
particularly high area of expression in a sub-region of the pons. The Es2
expression domain in the pons is shared with a Goosecoid-like gene ( Gscl)
which is located upstream of Es2 , and raises the possibility that the two
genes share regulatory elements and/or interact in this region of the
developing brain. This finding suggests that different genes in the deleted
region may be functionally related and might explain the occurrence of the
characteristic phenotype in patients with non-overlapping genetic lesions.
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2.
Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development 总被引:1,自引:1,他引:0
Saint-Jore B; Puech A; Heyer J; Lin Q; Raine C; Kucherlapati R; Skoultchi AI 《Human molecular genetics》1998,7(12):1841-1849
Velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS) are
characterized by a wide spectrum of abnormalities, including conotruncal
heart defects, velopharyngeal insufficiency, craniofacial anomalies and
learning disabilities. In addition, numerous other clinical features have
been described, including frequent psychiatric illness. Hemizygosity for a
1.5-3 Mb region of chromosome 22q11 has been detected in >80% of
VCFS/DGS patients. It is thought that a developmental field defect is
responsible for many of the abnormalities seen in these patients and that
the defect occurs due to reduced levels of a gene product active in early
embryonic development. Goosecoid-like ( GSCL ) is a homeobox gene which is
present in the VCFS/DGS commonly deleted region. The mouse homolog, Gscl,
is expressed in mouse embryos as early as E8.5. Gscl is related to
Goosecoid ( Gsc ), a gene required for proper craniofacial development in
mice. GSCL has been considered an excellent candidate for contributing to
the developmental defects in VCFS/DGS patients. To investigate the role of
Goosecoid-like in VCFS/DGS etiology, we disrupted the Gscl gene in mouse
embryonic stem cells and produced mice that transmit the disrupted allele.
Mice that are homozygous for the disrupted allele appear to be normal and
they do not exhibit any of the anatomical abnormalities seen in VCFS/DGS
patients. RNA in situ hybridization to mouse embryo sections revealed that
Gscl is expressed at E8.5 in the rostral region of the foregut and at E11.5
and E12.5 in the developing brain, in the pons region and in the choroid
plexus of the fourth ventricle. Although the gene inactivation experiments
indicate that haploinsufficiency for GSCL is unlikely to be the sole cause
of the developmental field defect thought to be responsible for many of the
abnormalities in VCFS/DGS patients, its localized expression during
development could suggest that hemizygosity for GSCL, in combination with
hemizygosity for other genes in 22q11, contributes to some of the
developmental defects as well as the behavioral anomalies seen in these
patients. The mice generated in this study should help in evaluating these
possibilities.
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3.
Functional analysis of Gscl in the pathogenesis of the DiGeorge and velocardiofacial syndromes 总被引:1,自引:1,他引:1
Wakamiya M; Lindsay EA; Rivera-Perez JA; Baldini A; Behringer RR 《Human molecular genetics》1998,7(12):1835-1840
Gscl encodes a Goosecoid-related homeodomain protein that is expressed
during mouse embryogenesis. In situ hybridization and immunohistochemistry
studies show that Gscl is expressed in the pons region of the developing
central nervous system and primordial germ cells. Gscl expression is also
detected in a subset of adult tissues, including brain, eye, thymus,
thyroid region, stomach, bladder and testis. Gscl is located within a
region of the mouse genome that is syntenic with the region commonly
deleted in DiGeorge and velocardiofacial syndrome (DGS/VCFS) patients.
DGS/VCFS patients have craniofacial abnormalities, cardiac outflow defects
and hypoplasia of the parathyroid gland and thymus due to
haploinsufficiency of a gene or genes located within the deleted region.
Thus, the genomic location of Gscl and its expression in a subset of the
tissues affected in DGS/VCFS patients suggest that Gscl may contribute to
the pathogenesis of DGS/VCFS. To determine the role of Gscl during mouse
embryogenesis and in DGS/VCFS, we have deleted Gscl by gene targeting in
mouse embryonic stem cells. Both Gscl heterozygous and Gscl null mice were
normal and fertile, suggesting that Gscl is not a major factor in DGS/VCFS.
Interestingly, expression of the adjacent Es2 gene in the pons region of
Gscl null fetuses was absent, suggesting that mutations within the DGS/VCFS
region can influence expression of adjacent genes. In addition, embryos
that lacked both Gscl and the related Gsc gene appeared normal. These
studies represent the first functional analysis of a DGS/VCFS candidate
gene in vivo. These Gscl null mice will be an important genetic resource
for crosses with other mouse models of the DGS/VCFS.
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Isolation of a gene expressed during early embryogenesis from the region of 22q11 commonly deleted in DiGeorge syndrome 总被引:3,自引:1,他引:3
Halford Stephanie; Wilson David I; DAW Sara C.M.; Roberts Cathrine; Wadey Roy; Kamath Shalan; Wickremasinghe Amal; Burn John; Goodship Judith; Mattel Marie-Genevieve; Moormon F.M.; Sclambler Peter J. 《Human molecular genetics》1993,2(10):1577-1582
DiGeorge syndrome (DGS) is one of several syndromes associatedwith deletions within the proximal long-arm of chromosome 22.The region of chromosome 22q11 responsible for the haplolnsufficiencysyndromes (the DiGeorge Critical Region or DGCR) has been mappedusing RFLPs, quantitative Southern blotting and FISH. Similardeletions are seen in the velo-cardio-facial syndrome (VCFS)and familial congenital heart defects. It Is not known whetherthe phenotypic spectrum is the result of the hemizygosity ofone gene or whether it is a consequence of contiguous genesbeing deleted. However, the majority of patients have a large(< =2Mb deletion). In this paper we report the isolationof a gene, lab name T10, encoding a serine/threonine rich proteinof unknown function which maps to the commonly deleted regionof chromosome 22q11. Studies in the mouse Indicate that it mapsto MMU16 and is expressed during early embryogenesis. Althoughnot mapping within the shortest region of overlap for DGS/VCFS,and therefore not the major gene Involved In DGS, the expressionpattern suggests that this gene may be involved in modifyingthe haplolnsufficient phenotype of hemizygous patients. 相似文献
7.
UFD1L, a developmentally expressed ubiquitination gene, is deleted in CATCH 22 syndrome 总被引:9,自引:2,他引:7
Pizzuti A; Novelli G; Ratti A; Amati F; Mari A; Calabrese G; Nicolis S; Silani V; Marino B; Scarlato G; Ottolenghi S; Dallapiccola B 《Human molecular genetics》1997,6(2):259-265
The CATCH 22 acronym outlines the main clinical features of 22q11.2
deletions (cardiac defects, abnormal facies, thymic hypoplasia, cleft
palate and hypocalcemia), usually found in DiGeorge (DGS) and velo-
cardio-facial (VCFS) syndromes. Hemizygosity of this region may also be the
cause of over 100 different clinical signs. The CATCH 22 locus maps within
a 1.5 Mb region, which encompasses several genes. However, no single defect
in 22q11.2 hemizygous patients can be ascribed to any gene so far isolated
from the critical region of deletion. We have identified a gene in the
CATCH 22 critical region, whose functional features and tissue-specific
expression suggest a distinct role in embryogenesis. This gene, UFD1L,
encodes the human homolog of the yeast ubiquitin fusion degradation 1
protein (UFD1p), involved in the degradation of ubiquitin fusion proteins.
Cloning and characterization of the murine homolog (Ufd1l) showed it to be
expressed during embryogenesis in the eyes and in the linear ear primordia.
These data suggest that the proteolytic pathway that recognizes ubiquitin
fusion proteins for degradation is conserved in vertebrates and that the
UFD1L gene hemizygosity is the cause of some of the CATCH 22-associated
developmental defects.
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Kimura MI Kazuki Y Kashiwagi A Kai Y Abe S Barbieri O Levi G Oshimura M 《Journal of human genetics》2004,49(5):273-277
The mouse Dlx5 gene encodes a distal-less-related DNA-binding homeobox protein first expressed during early embryonic development in anterior regions of mouse embryo and is located on chromosome 6, which is the syntenic region to the human chromosome 7q21–q31 imprinting cluster. Recently, its human homologue, DLX5, was identified to be imprinted and maternally expressed, at least in normal human lymphoblasts and in brain tissues. In our study, we analyzed the imprinting status of mouse Dlx5 by RT-PCR, first in the F1 of a reciprocal cross between two different mouse strains, and second in heterozygous Dlx5 mutant mice. Both approaches revealed that mouse Dlx5 followed a biallelic pattern of expression in brain tissue and in testis. Our findings suggest that the Dlx5 gene escapes genomic imprinting, at least in mice of certain genetic backgrounds. 相似文献
10.
Isolation and characterization of a novel transcript embedded within HIRA, a gene deleted in DiGeorge syndrome. 总被引:4,自引:0,他引:4
A Pizzuti G Novelli A Ratti F Amati R Bordoni P Mandich E Bellone E Conti M Bengala A Mari V Silani B Dallapiccola 《Molecular genetics and metabolism》1999,67(3):227-235
We have isolated a few cDNAs from different human tissues, transcribed from the first intron of HIRA, a gene deleted in the DiGeorge syndrome. These cDNAs are produced by an intronic gene (22k48) which is transcribed by the HIRA opposite strand and is itself arranged in exons and subjected to alternative splicing. The longest continuum cDNA sequence we obtained is 3.6 kb long and contains 3 different exons and 2 introns. 22k48 cDNA is composed of several tandemly arranged repeated elements (Alu, LINEs, CAn) surrounding a unique sequence. In situ hybridization showed the presence of 22k48 RNA in the cytoplasm of CNS and PNS neurons. 22k48 RNA is able to bind cytoplasmic proteins in the range of 45 to 60 kDa. 22k48 is a new member of the small group of genes that are transcribed but not translated, and its haploinsufficiency could contribute to the pathogenesis of the DiGeorge syndrome. 相似文献
11.
Marisela Jaquez Deborah A. Driscoll Mengrong Li Beverly S. Emanuel Isabel Hernandez Fransisca Jaquez Nicolas Lembert Joanny Ramirez Reuben Matalon 《American journal of medical genetics. Part A》1997,70(1):6-10
We report on an 8-year-old girl with an unbalanced 15;22 translocation and manifestations of DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), and other abnormalities. The main manifestations of our patient were feeding difficulties, respiratory infections, short stature, peculiar face with hypertelorism, prominent nose, abnormal ears, microstomia and crowded teeth, short broad neck and shield chest with pectus deformity and widely spaced nipples with abnormal fat distribution, heart defect, scoliosis, asymmetric limb development, abnormal hands and feet, and hyperchromic skin patches. Cytogenetic studies demonstrated a 45,XX,der(15)t(15;22)(p11.2;q11.2), -22 karyotype. Fluorescence in situ hybridization (FISH) studies confirmed loss of the proximal DiGeorge chromosomal region (DGCR). This case adds to the diversity of clinical abnormalities caused by deletions within 22q11.2. Am. J. Med. Genet. 70:6–10, 1997. © 1997 Wiley-Liss, Inc. 相似文献
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The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse 总被引:9,自引:5,他引:9
Human chromosome 15q11-q13 contains genes that are imprinted and expressed
from only one parental allele. Prader-Willi syndrome (PWS) is due to the
loss of expression of one or more paternally expressed genes on proximal
human chromosome 15q, most often by deletion or maternal uniparental
disomy. Several candidate genes and a putative imprinting centre have been
identified in the deletion region. We report that the human necdin-encoding
gene (NDN) is within the centromeric portion of the PWS deletion region,
between the two imprinted genes ZNF127 and SNRPN. Murine necdin is a
nuclear protein expressed exclusively in differentiated neurons in the
brain. Necdin is postulated to govern the permanent arrest of cell growth
of post-mitotic neurons during murine nervous system development. We have
localized the mouse locus Ndn encoding necdin to chromosome 7 in a region
of conserved synteny with human chromosome 15q11-q13, by genetic mapping in
an interspecific backcross panel. Furthermore, we demonstrate that
expression of Ndn is limited to the paternal allele in RNA from newborn
mouse brain. Expression of NDN is detected in many human tissues, with
highest levels of expression in brain and placenta. NDN is expressed
exclusively from the paternally inherited allele in human fibroblasts. Loss
of necdin gene expression may contribute to the disorder of brain
development in individuals with PWS.
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15.
T cell receptor repertoire and function in patients with DiGeorge syndrome and velocardiofacial syndrome 下载免费PDF全文
Pierdominici M Marziali M Giovannetti A Oliva A Rosso R Marino B Digilio MC Giannotti A Novelli G Dallapiccola B Aiuti F Pandolfi F 《Clinical and experimental immunology》2000,121(1):127-132
DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) are associated with chromosome 22q11.2 deletion. Limited information is available on the T cell receptor (TCR) Vbeta repertoire. We therefore investigated TCR Vbeta families in lymphocytes isolated from blood and thymic samples of seven patients with DGS and seven patients with VCFS, all with 22q11.2 deletion. We also studied activities related to TCR signalling including in vitro proliferation, anti-CD3-induced protein tyrosine phosphorylation, and susceptibility to apoptosis. Reduced CD3+ T cells were observed in most patients. Spontaneous improvement of T cell numbers was detected in patients, 3 years after the first study. Analysis of CD4+ and CD8+ TCR Vbeta repertoire in peripheral and thymic cells showed a normal distribution of populations even if occasional deletions were observed. Lymphoproliferative responses to mitogens were comparable to controls as well as anti-CD3-induced protein tyrosine phosphorylation. Increased anti-CD3-mediated apoptosis was observed in thymic cells. Our data support the idea that in patients surviving the correction of cardiac anomalies, the immune defect appears milder than originally thought, suggesting development of a normal repertoire of mature T cells. 相似文献
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Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development 总被引:4,自引:0,他引:4
DISC1 (Disrupted-In-Schizophrenia 1) has been associated with schizophrenia in multiple genetic studies. Studies from our laboratory have shown that Disc1, the mouse ortholog of DISC1, is highly expressed in the dentate gyrus of the hippocampus in the adult mouse brain. Because developmental dysfunction of the hippocampus is thought to play a major role in schizophrenia pathogenesis, and the dentate gyrus is a major locus for adult neurogenesis in the mouse, we investigated Disc1 expression during mouse brain development. Strikingly, Disc1 is strongly expressed in the hippocampus during all stages of hippocampal development, from embryonic day 14 through adulthood. Disc1 mRNA was detected in the dentate gyrus at all stages in which this structure was identifiable, as well as in the cornu ammonis (CA) fields of the hippocampus, the subiculum and adjacent entorhinal cortex, and the developing cerebral neocortex, hypothalamus, and olfactory bulbs, all of which also express Disc1 in the adult mouse brain. In addition, Disc1 mRNA was seen in regions of the developing mouse brain which do not express Disc1 during adulthood, regions including the bed nucleus of the stria terminalis, reticular thalamic nucleus and reuniens thalamic nucleus. These results demonstrate that Disc1 marks the hippocampus from its earliest stages, and suggest that developmental Disc1 dysfunction may lead to defects in hippocampal function that are associated with schizophrenia. 相似文献
19.
A novel gene has been characterized, designated C16orf5, with an unusually high content of proline residues (40% over 104 residues) at the N-terminus of the protein. The C-terminus
of the protein is also cysteine rich with 14 cysteine residues present. Analysis using Northern and dot blots showed that
the highest expression of this gene is in the brain. The gene was located on chromosome 16 at band p13.3 by FISH to metaphase
chromosomes. Southern blot analysis with a human–rodent somatic cell hybrid panel showed a location between the somatic hybrid
breakpoints 23HA and CY196. This gene comprises at least four exons and an open reading frame of 786 bp encoding a predicted
protein of 261 amino acids. Analysis of this protein using PSORTII predicted a nuclear localization.
Received: April 12, 1999 / Accepted: June 4, 1999 相似文献
20.
The gene encoding the stem cell antigen, CD34, is conserved in mouse and expressed in haemopoietic progenitor cell lines, brain, and embryonic fibroblasts. 总被引:14,自引:0,他引:14
The human haemopoietic cell surface antigen, CD34, is a 105 - 120 kd cell surface glycoprotein whose stage-specific expression by stem cells and lineage-specific progenitor cells suggests a role in regulating early events in blood cell differentiation. A murine gene and cDNA encoding a closely homologous protein have been isolated. The gene is organized in eight exons in 22 kb of DNA. The first exon lies in a GC- and CpG-rich island. The sequence of the gene and the cDNA predict a 382 amino acid-long protein containing an N-terminal signal peptide and one transmembrane region 73 amino acids from the C-terminus. The extracellular part of the protein contains: a 140 amino acid-long-N-terminal region, 40% of whose residues are serine or threonine potential attachment sites for O-linked carbohydrate, as well as five potential attachment sites for N-linked carbohydrate. Proximal to the extracellular membrane there is a 79 amino acid-long cysteine-rich region. The homology with the human sequence is highest in the intracellular domain (90% amino acid identity) and lowest in the N-terminal region (43% amino acid identity). The protein is not homologous with any other proteins currently in the databases. The expression of the murine gene by a number of haemopoietic progenitor cell lines suggests that the CD34 function in haemopoiesis may be conserved between man and mouse. The high level of expression in a number of embryonic fibroblast cell lines and in brain imply a function outside of haemopoiesis. 相似文献