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1.
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.
相似文献
2.
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
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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4.
De Luca A Pasini A Amati F Botta A Spalletta G Alimenti S Caccamo F Conti E Trakalo J Macciardi F Dallapiccola B Novelli G 《American journal of medical genetics》2001,105(6):529-533
Schizophrenia or schizoaffective disorders are often found in patients affected by DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of hemizygosity of chromosome 22q11.2. We evaluated the UFD1L gene, mapping within the DGS/VCFS region, as a potential candidate for schizophrenia susceptibility. UFD1L encodes for the ubiquitin fusion degradation 1 protein, which is expressed in the medial telencephalon during mouse development. Using case control, simplex families (trios), and functional studies, we provided evidence for association between schizophrenia and a single nucleotide functional polymorphism, -277A/G, located within the noncoding region upstream the first exon of the UFD1L gene. The results are supportive of UFD1L involvement in the neurodevelopmental origin of schizophrenia and contribute in delineating etiological and pathogenetic mechanism of the schizophrenia subtype related to 22q11.2 deletion syndrome. 相似文献
5.
Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects. 总被引:13,自引:3,他引:13 下载免费PDF全文
E Goldmuntz D Driscoll M L Budarf E H Zackai D M McDonald-McGinn J A Biegel B S Emanuel 《Journal of medical genetics》1993,30(10):807-812
Congenital conotruncal cardiac defects occur with increased frequency in patients with DiGeorge syndrome (DGS). Previous studies have shown that the majority of patients with DGS or velocardiofacial syndrome (VCFS) have a microdeletion within chromosomal region 22q11. We hypothesised that patients with conotruncal defects who were not diagnosed with DGS or VCFS would also have 22q11 deletions. Seventeen non-syndromic patients with one of three types of conotruncal defects most commonly seen in DGS or VCFS were evaluated for a 22q11 deletion. DNA probes from within the DiGeorge critical region were used. Heterozygosity at a locus was assessed using restriction fragment length polymorphisms. Copy number was determined by dosage analysis using Southern blot analysis of fluorescence in situ hybridisation of metaphase spreads. Five of 17 patients were shown to have a 22q11 deletion when evaluated by dosage analysis. This study shows a genetic contribution to the development of some conotruncal cardiac malformations and alters knowledge regarding the risk of heritability of these defects in certain cases. 相似文献
6.
Isolation of a new clathrin heavy chain gene with muscle-specific expression from the region commonly deleted in velo-cardio-facial syndrome 总被引:3,自引:4,他引:3
Sirotkin H; Morrow B; DasGupta R; Goldberg R; Patanjali SR; Shi G; Cannizzaro L; Shprintzen R; Weissman SM; Kucherlapati R 《Human molecular genetics》1996,5(5):617-624
Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome (DGS) are
developmental disorders characterized by a spectrum of phenotypes including
velopharyngeal insufficiency, conotruncal heart defects and facial
dysmorphology among others. Eighty to eighty-five percent of VCFS/DGS
patients are hemizygous for a portion of chromosome 22. It is likely that
the genes encoded by this region play a role in the etiology of the
phenotypes associated with the disorders. Using a cDNA selection protocol,
we isolated a novel clathrin heavy chain cDNA (CLTD) from the VCFS/DGS
minimally deleted interval. The cDNA encodes a protein of 1638 amino acids.
CLTD shares significant homology, but is not identical to the ubiquitously
expressed clathrin heavy chain gene. The CLTD gene also shows a unique
pattern of expression, having its maximal level of expression in skeletal
muscle. Velopharyngeal insufficiency and muscle weakness are common
features of VCFS patients. Based on the location and expression pattern of
CLTD, we suggest hemizygosity at this locus may play a role in the etiology
of one of the VCFS-associated phenotypes.
相似文献
7.
Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. 总被引:15,自引:4,他引:15 下载免费PDF全文
D A Driscoll J Salvin B Sellinger M L Budarf D M McDonald-McGinn E H Zackai B S Emanuel 《Journal of medical genetics》1993,30(10):813-817
Deletions of chromosome 22q11 have been seen in association with DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). In the present study, we analysed samples from 76 patients referred with a diagnosis of either DGS or VCFS to determine the prevalence of 22q11 deletions in these disorders. Using probes and cosmids from the DiGeorge critical region (DGCR), deletions of 22q11 were detected in 83% of DGS and 68% of VCFS patients by DNA dosage analysis, fluorescence in situ hybridisation, or by both methods. Combined with our previously reported patients, deletions have been detected in 88% of DGS and 76% of VCFS patients. The results of prenatal testing for 22q11 deletions by FISH in two pregnancies are presented. We conclude that FISH is an efficient and direct method for the detection of 22q11 deletions in subjects with features of DGS and VCFS as well as in pregnancies at high risk for a deletion. 相似文献
8.
Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse. 总被引:4,自引:0,他引:4
W L Kimber P Hsieh S Hirotsune L Yuva-Paylor H F Sutherland A Chen P Ruiz-Lozano S L Hoogstraten-Miller K R Chien R Paylor P J Scambler A Wynshaw-Boris 《Human molecular genetics》1999,8(12):2229-2237
Deletions or rearrangements of human chromosome 22q11 lead to a variety of related clinical syndromes such as DiGeorge syndrome (DGS) and velo--cardiofacial syndrome (VCFS). In addition, patients with 22q11 deletions have an increased incidence of schizophrenia and several studies have mapped susceptibility loci for schizophrenia to this region. Human molecular genetic studies have so far failed to identify the crucial genes or disruption mechanisms that result in these disorders. We have used gene targeting in the mouse to delete a defined region within the conserved DGS critical region (DGCR) on mouse chromosome 16 to prospectively investigate the role of the mouse DGCR in 22q11 syndromes. The deletion spans a conserved portion ( approximately 150 kb) of the proximal region of the DGCR, containing at least seven genes ( Znf74l, Idd, Tsk1, Tsk2, Es2, Gscl and Ctp ). Mice heterozygous for this deletion display no findings of DGS/VCFS in either inbred or mixed backgrounds. However, heterozygous mice display an increase in prepulse inhibition of the startle response, a manifestation of sensorimotor gating that is reduced in humans with schizophrenia. Homozygous deleted mice die soon after implantation, demonstrating that the deleted region contains genes essential for early post-implantation embryonic development. These results suggest that heterozygous deletion of this portion of the DGCR is sufficient for sensorimotor gating abnormalities, but not sufficient to produce the common features of DGS/VCFS in the mouse. 相似文献
9.
Amati F Conti E Novelli A Bengala M Diglio MC Marino B Giannotti A Gabrielli O Novelli G Dallapiccola B 《European journal of human genetics : EJHG》1999,7(8):903-909
Deletions of chromosome 22q11.2 have been associated with distinct phenotypes including DiGeorge syndrome (DGS) and velo-cardio-facial (VCFS) syndrome. These diseases result from a failure to form derivatives of the third and fourth branchial arches during development. DGS/VCFS deletions usually encompass about 3 Mb of genomic DNA in more than 90% of patients. However, deletion mapping studies have failed to demonstrate the existence of a single small region of overlap (SRO) and ruled out any obvious correlation between site or size of deletion and severity of clinical phenotype. We describe three patients carrying 'atypical' deletions presenting the DGS/VCFS phenotype. A comparative analysis of deletions in our patients and those previously published has suggested the existence of five distinct critical regions within the 22q11.2 locus. This observation argues that DGS/VCFS results from haploinsufficiency secondary to a complex and as yet unexplained molecular mechanism, probably involving chromatin effects in mediating gene expression throughout the entire region. 相似文献
10.
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.
相似文献
11.
Structural and mutational analysis of a conserved gene (DGSI) from the minimal DiGeorge syndrome critical region 总被引:2,自引:1,他引:2
Gong W; Emanuel BS; Galili N; Kim DH; Roe B; Driscoll DA; Budarf ML 《Human molecular genetics》1997,6(2):267-276
The majority of patients with DiGeorge syndrome (DGS), velocardiofacial
syndrome (VCFS), conotruncal anomaly face syndrome (CTAFS) and some
individuals with familial or sporadic conotruncal cardiac defects have
hemizygous deletions of chromosome 22. Most patients with these disorders
share a common large deletion, spanning > 1.5 Mb within 22q11.21-q11.23.
Recently, the smallest region of deletion overlap has been narrowed to a
250 kb area, the minimal DGS critical region (MDGCR), which includes the
locus D22S75 (N25). We have isolated and characterized a novel, highly
conserved gene, DGSI, within the MDGCR. DGSI has 10 exons and nine introns
encompassing 1702 bp of cDNA sequence and 11 kb of genomic DNA. The encoded
protein has 476 amino acids with a predicted mol. wt of 52.6 kDa. The
intron-exon boundaries have been analyzed and conform to the consensus
GT/AG motif. The corresponding murine Dgsi has been isolated and localized
to proximal mouse chromosome 16. The mouse gene contains the same number of
exons and introns, and the predicted protein has 479 amino acids with 93.2%
identity to that of the human DGSI gene. By database searching, both genes
have significant homology to a Caenorhabditis elegans hypothetical protein,
F42H10.7. Further, mutation analysis has been performed in 16 patients, who
have no detectable 22q11.2 deletion and some of the characteristic clinical
features of DGS/VCFS. We have detected eight sequence variants in DGSI.
These occurred in the 5'- untranslated region, the coding region and the
intronic regions adjacent to the intron-exon boundaries of the gene. Seven
of the eight variants were also present in normal controls or unaffected
family members, suggesting they may not be of etiologic significance.
相似文献
12.
David Kelly Rosalie Goldberg David Wilson Elizabeth Lindsay Alisoun Carey Judith Goodship John Burn Ian Cross Robert J. Shprintzen Peter J. Scambler 《American journal of medical genetics. Part A》1993,45(3):308-312
The velo-carido-facial syndrome (VCFS) and DiGeorge sequence (DGS) have many similar phenotypic characteristics, suggesting that in some cases they share a common cause. DGS is known to be associated with monosomy for a region of chromosome 22q11, and DNA probes have been shown to detect these deletions even in patients with apparently normal chromosomes. Twelve patients with VCFS were examined and monsomy for a region of 22q11 was found in all patients. The DNA probes used in this study could not distinguish the VCFS locus and the DGS locus, indicating that the genes involved in these haplo-insufficiencies are closely linked, and may be identical. The phenotypic variation of expression in VCFS and DGS may indicate that patients without the full spectrum of VCFS abnormalities but with some manifestations of the disorder may also have 22q11 deletions. © 1993 Wiley-Liss, Inc. 相似文献
13.
Marie-France Portno? 《European journal of medical genetics》2009,52(2-3):88-93
The chromosome 22q11.2 region has long been implicated in genomic diseases. The low-copy repeats spanning the region predispose to homologous recombination events, and mediate nonallelic homologous recombinations that result in rearrangements of 22q11.2. Chromosome duplication of the region that is deleted in patients with DGS/VCFS has been reported, establishing a new genomic duplication syndrome complementary to the 22q11.2 deletion syndrome. Recent data suggest that the frequency of the microduplications 22q11.2 is approximately half that of the deletions. Up till now about 50 unrelated cases of 22q11.2 duplications have been reported. A high frequency of familial duplications has been reported. The phenotype of patients is extremely variable, ranging from multiple defects to mild learning difficulties, sharing features with DGS/VCFS, including heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and with some individuals being essentially normal. The basis of phenotype variability remains to be elucidated. The large majority of affected individuals have identical 3 Mb duplications. The 22q11.2 microduplication syndrome can be diagnosed with high accuracy by interphase fluorescence in situ hybridization, and several other molecular laboratory techniques. The 3 Mb duplication encompasses a region containing 40 genes including the TBX1 gene that has been shown to be the major disease gene responsible for the DGS/VCFS. Interestingly, TBX1 gain-of-function mutations, resulting in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions, have been observed, confirming that TBX1 overexpression might be responsible for the dup22q11.2 disorder. 相似文献
14.
L Edelmann R K Pandita E Spiteri B Funke R Goldberg N Palanisamy R S Chaganti E Magenis R J Shprintzen B E Morrow 《Human molecular genetics》1999,8(7):1157-1167
The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der() syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease. 相似文献
15.
Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation 总被引:5,自引:2,他引:5
Holmes SE; Riazi MA; Gong W; McDermid HE; Sellinger BT; Hua A; Chen F; Wang Z; Zhang G; Roe B; Gonzalez I; McDonald-McGinn DM; Zackai E; Emanuel BS; Budarf ML 《Human molecular genetics》1997,6(3):357-367
16.
Alberti A Romano C Falco M Calì F Schinocca P Galesi O Spalletta A Di Benedetto D Fichera M 《Clinical genetics》2007,71(2):177-182
The 22q11.2 microduplication syndrome is caused by non-allelic homologous recombination mediated by misalignments of low copy repeats located in the region deleted in the DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS). The variable phenotype of such condition, consisting in a combination of dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement, is caused usually in 90% of cases by a 3 Mb deletion or in a minority of cases (7%) by a 1.5 Mb deletion. The most common reciprocal event of deletion is the 3 Mb duplication, reported more recently with a variable phenotype, ranging from multiple defects to normality. In this study, we report a 2.5-year-old girl with cognitive deficits and dysmorphic facial features such as superior placement of eyebrows, upslanting palpebral fissures, widely spaced eyes, broad nasal bridge and epicanthal folds. Fluorescent in situ hybridization for DGS/VCFS region on metaphase chromosomes did not show any apparent anomaly. Subsequent array comparative genomic hybridization study, confirmed by multiplex ligation-dependent probe assay and microsatellite analysis, disclosed a 1.5 Mb de novo 22q11.21 duplication concerning the same chromosomal region deleted in a minority of patients with DGS. These findings identify the minimal duplicated region leading to this emerging syndrome. 相似文献
17.
DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 gene 总被引:5,自引:0,他引:5
Conti E Grifone N Sarkozy A Tandoi C Marino B Digilio MC Mingarelli R Pizzuti A Dallapiccola B 《European journal of human genetics : EJHG》2003,11(4):349-351
The role of the 22q11 region genes, and among them TBX1, in nonsyndromic conotruncal defects (CTDs) is still unclear. Mice hemizygous at the Tbx1 locus show a remarkable incidence of heart outflow tract anomalies, of the same type commonly found in DiGeorge/Velo-cardio-facial syndrome (DGS/VCFS). Mutation analysis of the TBX1 gene in isolated, nonsyndromic CTDs has not demonstrated any functional pathogenetic variation so far. We screened the TBX1 gene in 41 patients affected by nonsyndromic CTDs of the DGS/VCFS subtype, principally "atypical" tetralogy of Fallot. Besides a few polymorphisms, we did not find any pathogenetic variation. These results do not support a major role of the TBX1 gene as responsible for human nonsyndromic CTDs. 相似文献
18.
Giuseppe Scir Bruno Dallapiccola Paola Iannetti Francesco Bonaiuto Cinzia Galasso Rita Mingarelli Brunetto Boscherini 《American journal of medical genetics. Part A》1994,52(4):478-482
We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The pheno-typic manifestations of the observed patients were consistent with velo-cardio-facial syndrome (VCFS). A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome. The presence of certain traits of DGS/VCFS should lead to investigations of the parathyroid function and molecular analysis of the 22q11 region hybridization studies. © 1994 Wiley-Liss, Inc. 相似文献
19.
Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects. 总被引:1,自引:0,他引:1
B Funke J A Epstein L K Kochilas M M Lu R K Pandita J Liao R Bauerndistel T Schüler H Schorle M C Brown J Adams B E Morrow 《Human molecular genetics》2001,10(22):2549-2556
Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients. 相似文献
20.
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.
相似文献