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2.
Am J Med Genet A ; 120A(1): 49-58, 2003 Jul 01.
Article in English | MEDLINE | ID: mdl-12794692

ABSTRACT

Greig cephalopolysyndactyly (GCPS) (OMIM 175700) is an autosomal dominant disorder characterized by a distinct combination of craniofacial, hand and foot malformations. In this report, clinical and radiological findings of 12 patients with GCPS derived from 4 independent families and 3 sporadic cases with documented GLI3 mutations are presented with particular emphasis on inter- and intrafamilial variability. In a particularly instructive family in which 9 members of 4 generations could be studied clinically and molecularly, a missense mutation (R625W) is transmitted and shows a partially penetrant pattern. In a branch of the family, the GCPS phenotype skips a generation via a normal female carrier without clinical signs providing evidence that GCPS does not always manifest full penetrance as generally supposed.


Subject(s)
DNA-Binding Proteins/genetics , Mutation , Nerve Tissue Proteins , Transcription Factors/genetics , Alleles , Craniofacial Abnormalities/diagnostic imaging , Craniofacial Abnormalities/genetics , DNA Mutational Analysis , Facies , Family Health , Female , Genes, Dominant , Genetic Markers , Heterozygote , Humans , In Situ Hybridization, Fluorescence , Kruppel-Like Transcription Factors , Limb Deformities, Congenital/diagnostic imaging , Limb Deformities, Congenital/genetics , Male , Mutation, Missense , Pedigree , Penetrance , Phenotype , Polydactyly/diagnostic imaging , Polydactyly/genetics , Polymorphism, Single-Stranded Conformational , Radiography , Syndactyly/diagnostic imaging , Syndactyly/genetics , Syndrome , Zinc Finger Protein Gli3
5.
Am J Med Genet ; 90(3): 239-42, 2000 Jan 31.
Article in English | MEDLINE | ID: mdl-10678662

ABSTRACT

An unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia was observed in a newborn infant. A history of digital anomalies in the father and grandfather lead to the diagnosis of dominantly inherited Greig cephalopolysyndactyly syndrome (GCPS, MIM #175700). Having explained the digital findings and macrocephaly, the skeletal changes were thought to fit best congenital spondyloepiphyseal dysplasia (SEDC MIM #183900), a type II collagen disorder. Molecular analysis confirmed the presence of two dominant mutations in the propositus: a GLI3 mutation (E543X), which was present also in the father and grandfather, and a de novo COL2A1 mutation leading to a G973R substitution. Thus, this boy combined the syndactyly-macrocephaly phenotype of Greig cephalosyndactyly syndrome with a severe form of spondyloepiphyseal dysplasia caused by the structural defect in type II collagen. The diagnostic difficulties posed by the combination of two genetic disorders and the contribution of molecular diagnostics are well illustrated by this case.


Subject(s)
Abnormalities, Multiple/genetics , Collagen/genetics , DNA-Binding Proteins/genetics , Genes, Dominant , Nerve Tissue Proteins , Point Mutation , Repressor Proteins , Transcription Factors/genetics , Xenopus Proteins , Female , Humans , Infant , Kruppel-Like Transcription Factors , Lod Score , Male , Osteochondrodysplasias/genetics , Pedigree , Skull/abnormalities , Zinc Finger Protein Gli3
6.
Ann N Y Acad Sci ; 923: 25-42, 2000.
Article in English | MEDLINE | ID: mdl-11193762

ABSTRACT

Rabbit uteroglobin is the founder member of a family of mammalian proteins that has expanded to more than 20 members within the last few years. All members are small, secretory, rarely glycosylated dimeric proteins with unclear physiological functions and are mainly expressed in mucosal tissues. A phylogenetic analysis shows that the family can be grouped into five subfamilies, A to E. Subfamily A contains rabbit uteroglobin and its orthologues from various species; most of these have been described to form antiparallel homodimers via two intermolecular disulfide bonds. All other subfamily members contain a third conserved cysteine and, from existing biochemical data, it can be predicted that a member of subfamily B or C will likely form heterodimers with a partner from subfamily E or D, respectively. Besides the mentioned cysteines, only one central lysine is conserved in all family members. In the known uteroglobin structures, this lysine forms an exposed salt bridge with an aspartate side chain, which is conserved in almost all sequences. Using radiation hybrid mapping and P1 clone analysis and utilizing data from the human genome project, we show that all known five human family members (Clara cell 10-kDa protein, lipophilins A and B, lacryglobin, mammaglobin) and a new member, we call lymphoglobin, are localized on chromosome 11q12.2 in a dense cluster spanning not more than approximately 400 kbp.


Subject(s)
Chromosomes, Human, Pair 11/genetics , Genitalia, Female/metabolism , Globins/genetics , Multigene Family/physiology , Sequence Homology , Uteroglobin/genetics , Amino Acid Sequence/genetics , Animals , Female , Genitalia, Female/cytology , Humans , Mammaglobin A , Molecular Sequence Data , Myelin Proteins/genetics , Neoplasm Proteins/genetics , Phylogeny , Proteolipids/genetics , Radiation Hybrid Mapping , Secretoglobins , Uteroglobin/chemistry
7.
Hum Mol Genet ; 8(9): 1769-77, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10441342

ABSTRACT

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.


Subject(s)
Craniofacial Abnormalities/genetics , DNA-Binding Proteins/genetics , Limb Deformities, Congenital/genetics , Mutation , Nerve Tissue Proteins , Repressor Proteins , Transcription Factors/genetics , Xenopus Proteins , Animals , DNA Mutational Analysis , Drosophila , Humans , Kruppel-Like Transcription Factors , Recombinant Fusion Proteins , Sequence Deletion , Syndrome , Transcriptional Activation , Transfection , Tumor Cells, Cultured , Zinc Finger Protein Gli3 , Zinc Fingers/genetics
8.
Hum Mol Genet ; 6(11): 1979-84, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9302279

ABSTRACT

Greig cephalopolysyndactyly syndrome (GCPS, MIM 175700) is a rare autosomal dominant developmental disorder characterized by craniofacial abnormalities and post-axial and pre-axial polydactyly as well as syndactyly of hands and feet. Human GLI3, located on chromosome 7p13, is a candidate gene for the syndrome because it is interrupted by translocation breakpoints associated with GCPS. Since hemizygosity of 7p13 resulting in complete loss of one copy of GLI3 causes GCPS as well, haploinsufficiency of this gene was implicated as a mechanism to cause this developmental malformation. To determine if point mutations within GLI3 could be responsible for GCPS we describe the genomic sequences at the boundaries of the 15 exons and primer pair sequences for mutation analysis with polymerase chain reaction-based assays of the entire GLI3 coding sequences. In two GCPS cases, both of which did not exhibit obvious cytogenetic rearrangements, point mutations were identified in different domains of the protein, showing for the first time that Greig syndrome can be caused by GLI3 point mutations. In one case a nonsense mutation in exon X generates a stop codon truncating the protein in the C-H link of the first zinc finger. In the second case a missense mutation in exon XIV causes a Pro-->Ser replacement at a position that is conserved among GLI genes from several species altering a potential phosphorylation site.


Subject(s)
Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Nerve Tissue Proteins , Point Mutation , Repressor Proteins , Transcription Factors , Xenopus Proteins , Chromosomes, Human, Pair 7 , Craniofacial Abnormalities/genetics , DNA Mutational Analysis , Genome , Humans , Kruppel-Like Transcription Factors , Polydactyly/genetics , Syndactyly/genetics , Syndrome , Zinc Finger Protein Gli3
9.
Clin Genet ; 52(6): 436-41, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9520255

ABSTRACT

A male had several features of Greig cephalopolysyndactyly syndrome (GCPS) and significant developmental delay. He was found to have a de novo chromosomal deletion of chromosome no. 7 involving p13; this resulted in loss of the zinc finger gene, GLI3, which is the candidate gene in this syndrome. Modification of the CGPS phenotype in a sporadic case emphasizes the importance of searching for a chromosomal origin of this autosomal dominant disorder. Detection of a chromosomal deletion in these patients may be associated with a poor prognosis from the standpoint of cognitive development, and the potential for other structural abnormalities not normally associated with GCPS.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Deletion , Chromosomes, Human, Pair 7 , Craniofacial Abnormalities/genetics , Intellectual Disability/genetics , Syndactyly/genetics , Humans , In Situ Hybridization, Fluorescence , Infant , Male , Phenotype , Polydactyly/genetics , Syndrome , Zinc Fingers/genetics
10.
J Biol Chem ; 271(49): 31470-8, 1996 Dec 06.
Article in English | MEDLINE | ID: mdl-8940160

ABSTRACT

Zyxin is a component of adhesion plaques that has been suggested to perform regulatory functions at these specialized regions of the plasma membrane. Here we describe the isolation and characterization of cDNAs encoding human and mouse zyxin. Both the human and mouse zyxin proteins display a collection of proline-rich sequences as well as three copies of the LIM domain, a zinc finger domain found in many signaling molecules. The human zyxin protein is closely related in sequence to proteins implicated in benign tumorigenesis and steroid receptor binding. Antibodies raised against human zyxin recognize an 84-kDa protein by Western immunoblot analysis. The protein is localized at focal contacts in adherent erythroleukemia cells. By Northern analysis, we show that zyxin is widely expressed in human tissues. The zyxin gene maps to human chromosome 7q32-q36.


Subject(s)
Cell Adhesion , Metalloproteins/chemistry , Zinc Fingers , Amino Acid Sequence , Animals , Base Sequence , Blotting, Western , Chromosome Mapping , Cytoskeletal Proteins , DNA, Complementary/chemistry , DNA, Complementary/isolation & purification , Glycoproteins , Humans , Mice , Molecular Sequence Data , Polymerase Chain Reaction , RNA, Messenger/metabolism , Zyxin
12.
Gene ; 169(2): 179-85, 1996 Mar 09.
Article in English | MEDLINE | ID: mdl-8647443

ABSTRACT

The intron-containing gene encoding human ribosomal protein S3a (hRPS3a) was isolated by utilizing a PCR-based strategy to detect a gene-specific intron which was subsequently used as a probe for cloning of the entire gene. The hRPS3a gene is composed of six exons and five introns spanning 5013 bp. As described for other hRP-encoding genes, the promoter lacks a canonical TATA sequence and a defined CAAT box. Primer extension experiments, as well as cell-free transcription, revealed that a cytosine functions as the major transcription start point in a polypyrimidine region, but a guanosine at position -1 was also able to initiate transcription. Hybridization analysis of chromosomal DNA from a panel of human-rodent somatic cell hybrids revealed that hRPS3a is encoded by a single locus in the human genome, present on chromosome 4.


Subject(s)
Ribosomal Proteins/genetics , Transcription, Genetic/genetics , Amino Acid Sequence , Animals , Base Sequence , Cell-Free System , Chromosome Mapping , Cricetinae , DNA/genetics , Gene Dosage , Gene Expression , HeLa Cells , Humans , Hybrid Cells , Introns/genetics , Mice , Molecular Sequence Data , Polymerase Chain Reaction , Ribosomal Proteins/chemistry
14.
Genomics ; 22(2): 439-48, 1994 Jul 15.
Article in English | MEDLINE | ID: mdl-7806232

ABSTRACT

Toward the construction of a complete physical map of human chromosome 7, we have localized 725 YAC clones to cytogenetically defined regions using fluorescence in situ hybridization (FISH) and by screening with DNA markers of known chromosomal locations. These chromosome 7-specific YAC clones are part of a library constructed with DNA isolated from monochromosomal 7 human-hamster somatic cell hybrid lines. The FISH mapping for 575 clones was accomplished by using "Alu-PCR" amplified YAC DNA against metaphase chromosome spreads made from a monochromosomal 7 human-mouse somatic cell hybrid line. Hybridization- or PCR-based screening of previously mapped DNA markers was performed for the mapping of 221 YAC clones. There was excellent correlation between the map locations obtained for the 71 YACs localized with both methods. All of the regionally localized YAC clones are valuable reagents for mapping and identification of disease genes on human chromosome 7.


Subject(s)
Chromosomes, Artificial, Yeast , Chromosomes, Human, Pair 7 , Genetic Markers , Animals , Chromosome Mapping , Cricetinae , Gene Library , Humans , Hybrid Cells , In Situ Hybridization, Fluorescence , Polymerase Chain Reaction
15.
Genomics ; 16(3): 649-54, 1993 Jun.
Article in English | MEDLINE | ID: mdl-8325638

ABSTRACT

PCR analysis of chromosomal DNA from a panel of human-rodent somatic cell hybrids revealed that the five human H1 histone genes H1.1 to H1.5 and the gene encoding the testis-specific H1t subtype, all of which form clusters with core histone genes, are located on chromosome 6. The H1(0) subtype, which is not neighbored by core histone genes, maps to chromosome 22. Fluorescence in situ hybridization with human metaphase chromosomes and PCR analysis of somatic cell hybrid DNA carrying only fragments of chromosome 6 revealed the region 6p21.1 to 6p22.2 as the histone gene cluster region.


Subject(s)
Chromosomes, Human, Pair 22 , Chromosomes, Human, Pair 6 , Histones/genetics , Multigene Family , Animals , Base Sequence , DNA , Humans , Hybrid Cells , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Polymerase Chain Reaction
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