RESUMEN
Deletions within HSA band 4p16.3 cause Wolf-Hirschhorn syndrome (WHS), which comprises mental retardation and developmental defects. A WHS critical region (WHSCR) of approximately 165 kb has been defined on the basis of 2 atypical interstitial deletions; however, genotype-phenotype correlation remains controversial, due to the large size of deletion usually involving several megabases. We report on the first known patient with a small de novo interstitial deletion restricted to the WHSCR who presented with a partial WHS phenotype consisting only of low body weight for height, speech delay, and minor facial anomalies; shortness of stature, microcephaly, seizures and mental retardation were absent. The deletion was initially demonstrated by FISH analysis, and breakpoints were narrowed with a "mini-FISH" technique using 3-5 kb amplicons. A breakpoint-spanning PCR assay defined the distal breakpoint as disrupting the WHSC1 gene within intron 5, exactly after an AluJb repeat. The proximal breakpoint was not found to be associated with a repeated sequence or a known gene. The deletion encompasses 191.5 kb and includes WHSC2, but not LETM1. Thus, manifestations attributable to this deletion are reduced weight for height, minor facial anomalies, ADHD and some learning and fine motor deficiencies, while seizures may be associated with deletions of LETM1.
Asunto(s)
Anomalías Múltiples/genética , Proteínas Portadoras , Deleción Cromosómica , Proteínas/genética , Proteínas Represoras , Peso Corporal , Niño , Anomalías Craneofaciales , Análisis Citogenético , Discapacidades del Desarrollo , Proteínas del Grupo de Alta Movilidad/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual , Trastornos del Desarrollo del Lenguaje , Masculino , Mapeo Físico de Cromosoma , Síndrome , Factores de Elongación TranscripcionalRESUMEN
We report on a clinical-genetic study of 16 Wolf-Hirschhorn syndrome (WHS) patients. Hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis (11 patients) or by molecular probes on apparently normal chromosomes (4 patients). One patient had normal chromosomes without a detectable molecular deletion within the WHS "critical region." In each deleted patient, the deletion was demonstrated to be terminal by fluorescence in situ hybridization (FISH). The proximal breakpoint of the rearrangement was established by prometaphase chromosome analysis in cases with a visible deletion. It was within the 4p16.1 band in six patients, apparently coincident with the distal half of this band in five patients. The extent of each of the four submicroscopic deletions was established by FISH analyses with a set of overlapping cosmid clones spanning the 4p16.3 region. We found ample variations in both the size of the deletions and the position of the respective breakpoints. The precise definition of the cytogenetic defect permitted an analysis of the genotype-phenotype correlations in WHS, leading to the proposal of a set of minimal diagnostic criteria, which in turn may facilitate the selection of critical patients in the search for the gene(s) responsible for this disorder. We observed that genotype-phenotype correlations in WHS mostly depend on the size of the deletion, a deletion of <3.5 Mb resulting in a mild phenotype, in which malformations are absent. The absence of a detectable molecular deletion is still consistent with a WHS diagnosis. Based on these observations a "minimal" WHS phenotype was inferred, the clinical manifestations of which are restricted to the typical facial appearance, mild mental and growth retardation, and congenital hypotonia.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 4 , Adolescente , Encéfalo/anomalías , Niño , Preescolar , Cósmidos , Sondas de ADN , Discapacidades del Desarrollo/genética , Facies , Femenino , Eliminación de Gen , Genotipo , Humanos , Hibridación Fluorescente in Situ , Lactante , Discapacidad Intelectual/genética , Cariotipificación , Riñón/anomalías , Masculino , Modelos Genéticos , Fenotipo , Convulsiones/genética , SíndromeRESUMEN
Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterized by mental and developmental defects resulting from the absence of a segment of one chromosome 4 short arm (4p16.3). Recently, Pitt-Rogers-Danks syndrome (PRDS), which is also due to a deletion of chromosome 4p16.3, has been shown to be allelic to WHS. Due to the complex and variable expression of these disorders, it is thought that WHS/PRDS results from a segmental aneusomy of 4p resulting in haploinsufficieny of an undefined number of genes that contribute to the phenotype. In an effort to identify genes that contribute to human development and whose absence may contribute to the phenotype associated with these syndromes, we have generated a transcript map of the 165-kb critical region and have identified a number of potential genes. One of these genes, WHSC2, which was identified with the IMAGE cDNA clone 53283, has been characterized. Sequence analysis defined an open reading frame of 1584 bp (528 amino acids), and transcript analysis detected a 2.4-kb transcript in all fetal and adult tissues tested. In parallel, the mouse homologue was isolated and characterized. Mouse sequence analysis and the pattern of expression are consistent with the clone being the murine equivalent of the human WHSC2 gene (designated Whsc2h). The data from sequence and transcript analysis of this new human gene in combination with the lack of significant similarity to proteins of known function imply that it represents a novel gene. Most importantly, its location within the WHSCR suggests that this gene may play a role in the phenotype of the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome.
Asunto(s)
Cromosomas Humanos Par 4/genética , Genes/genética , Trastornos del Crecimiento/genética , Discapacidad Intelectual/genética , Proteínas/genética , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Adulto , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Complementario/química , ADN Complementario/genética , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario y Fetal , Exones , Femenino , Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Hibridación in Situ , Intrones , Masculino , Ratones , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Síndrome , Distribución Tisular , Transcripción Genética , Factores de Elongación TranscripcionalRESUMEN
Chromosome imbalance affecting the short arm of chromosome 4 results in a variety of distinct clinical conditions. Most of them share a number of manifestations, such as mental retardation, microcephaly, pre- and post-natal growth retardation, anteverted and low-set ears, that can be considered as nonspecific signs, generally attributable to gene dosage impairment. On the other hand, more distinctive phenotypic traits correlate with the segmental aneuploidy. Duplications of the distal half of 4p give rise to the partial trisomy 4 syndrome, characterized by a "boxer" nose configuration and deep-set eyes. These signs are usually observed even in cases of small terminal duplications. Haploinsufficiency of 4p16.3 results in the so-called Wolf-Hirschhorn (WH) syndrome, a contiguous gene syndrome characterized by maxillary hypoplasia, large and protruding eyes, high nasal bridge, skeletal abnormalities, and midline defects. The smallest overlapping deletion described so far as a cause of this condition is only 165 kb long, suggesting that one or a few genes in this region act as "master" regulators of different developmental pathways. A "tandem" duplication of 4p16.1p16.3 was detected in association with a subtle deletion of 4p16.3pter on the same chromosome in a patient with the WH phenotype. The 3.2 Mb deletion, spanning the genomic region from the vicinity of D4S43 to the telomere, encompasses the recently delimited "WHS critical region" [Wright et al., 1997: Hum. Mol. Genet. 6:317-324]. This unusual chromosome rearrangement resulted in WH phenotype, clinical manifestations of partial 4p trisomy being mild or absent. This observation led us to speculate that the regulatory gene/genes in the critical WH region affect the expression of other genes in a dose-dependent manner. Haploinsufficiency of this region could be more deleterious than various partial trisomies.
Asunto(s)
Cromosomas Humanos Par 4/genética , Preescolar , Bandeo Cromosómico , Eliminación de Gen , Duplicación de Gen , Humanos , Hibridación Fluorescente in Situ , Masculino , Repeticiones de Microsatélite , Modelos Genéticos , Fenotipo , SíndromeAsunto(s)
Cromosomas Humanos Par 10 , Cromosomas Humanos Par 4 , Proteínas de Unión al ADN , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , Clonación Molecular , Humanos , Internet , Proteínas con Dominio LIM , Datos de Secuencia Molecular , FenotipoRESUMEN
Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The smallest region of overlap between WHS patients, the WHS critical region, has been confined to 165 kb, of which the complete sequence is known. We have identified and studied a 90 kb gene, designated as WHSC1 , mapping to the 165 kb WHS critical region. This 25 exon gene is expressed ubiquitously in early development and undergoes complex alternative splicing and differential polyadenylation. It encodes a 136 kDa protein containing four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash -encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern and its mapping to the critical region led us to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS. Finally, as a serendipitous finding, of the t(4;14) (p16.3;q32.3) translocations recently described in multiple myelomas, at least three breakpoints merge the IgH and WHSC1 genes, potentially causing fusion proteins replacing WHSC1 exons 1-4 by the IgH 5'-VDJ moiety.
Asunto(s)
Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 4/genética , Regulación del Desarrollo de la Expresión Génica , Cadenas Pesadas de Inmunoglobulina/genética , Mieloma Múltiple/genética , Proteínas/genética , Translocación Genética , Secuencia de Aminoácidos , Animales , Composición de Base , Northern Blotting , Proteínas Cromosómicas no Histona , Proteínas de Unión al ADN , Genes de Inmunoglobulinas , Genes Relacionados con las Neoplasias , Chaperonas de Histonas , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Biosíntesis de Proteínas , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Síndrome , Factores de TranscripciónRESUMEN
Wolf-Hirschhorn syndrome (WHS), a multiple congenital malformation syndrome, and Pitt-Rogers-Danks syndrome (PRDS), a rare condition with similar anomalies, were previously thought to be clinically distinct conditions. While WHS has long been associated with deletions near the terminus of 4p, several recent studies have shown PRDS is associated with deletions in 4p16.3. In this paper we evaluate three patients, two described as PRDS and one diagnosed as WHS. We demonstrate that the molecular defects associated with the two syndromes show a considerable amount of overlap. We conclude that both of these conditions result from the absence of similar, if not identical, genetic segments and propose that the clinical differences observed between these two syndromes are likely the result of allelic variation in the remaining homologue.
Asunto(s)
Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 4/genética , Anomalías Congénitas/genética , Adolescente , Alelos , Línea Celular , Trastornos de los Cromosomas , Cósmidos , Femenino , Eliminación de Gen , Humanos , Hibridación Fluorescente in SituRESUMEN
PDZ motifs are protein-protein interaction domains that often bind to COOH-terminal peptide sequences. The two PDZ proteins characterized in skeletal muscle, syntrophin and neuronal nitric oxide synthase, occur in the dystrophin complex, suggesting a role for PDZ proteins in muscular dystrophy. Here, we identify actinin-associated LIM protein (ALP), a novel protein in skeletal muscle that contains an NH2-terminal PDZ domain and a COOH-terminal LIM motif. ALP is expressed at high levels only in differentiated skeletal muscle, while an alternatively spliced form occurs at low levels in the heart. ALP is not a component of the dystrophin complex, but occurs in association with alpha-actinin-2 at the Z lines of myofibers. Biochemical and yeast two-hybrid analyses demonstrate that the PDZ domain of ALP binds to the spectrin-like motifs of alpha-actinin-2, defining a new mode for PDZ domain interactions. Fine genetic mapping studies demonstrate that ALP occurs on chromosome 4q35, near the heterochromatic locus that is mutated in fascioscapulohumeral muscular dystrophy.
Asunto(s)
Actinina/metabolismo , Cromosomas Humanos Par 4 , Proteínas de Microfilamentos/biosíntesis , Proteínas de Microfilamentos/química , Músculo Esquelético/metabolismo , Espectrina/química , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Mapeo Cromosómico , Variación Genética , Humanos , Cariotipificación , Proteínas con Dominio LIM , Proteínas de Microfilamentos/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
Wolf-Hirschhorn syndrome (WHS) caused by 4p16.3 deletions comprises growth and mental retardation, distinct facial appearance and seizures. This study characterized a subtle interstitial deletion of 4p16.3 in a girl with mild retardation and possessing facial traits characteristic of WHS. The patient had generalized seizures in conjunction with fever at 3 and 5 years of age. Fluorescence in situ hybridization (FISH) with a series of markers in the 4p16.3 region showed that the interstitial deletion in this patient was between the probes D4S96 and D4S182, enabling the size of the deletion to be estimated as less than 1.9 Mb. This is the smallest interstitial deletion of 4p16.3 which has been reported. The patient contributes to a refinement of the phenotypic map of the WHS region in 4p16.3. The critical region for the characteristic facial changes of WHS, failure to thrive and developmental delay is now localized to a region of less than 700 kb. The mental retardation of this patient was mild suggesting that small interstitial deletion may have less severe phenotypic consequences.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 4 , Cara/anomalías , Trastornos del Crecimiento/genética , Discapacidad Intelectual/genética , Convulsiones/genética , Preescolar , Mapeo Cromosómico , Femenino , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , SíndromeRESUMEN
Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition characterized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment previously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an intensive investigation of the developmental role of all the genes contained within it would be daunting and expensive. Further refinement in the definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this study, we have utilized fluorescence in situ hybridization to further characterize a WHS patient previously demonstrated to have an interstitial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating several genes previously proposed as contributing to this syndrome and allows further research to focus on a more restricted region of the genome and a limited set of genes for their role in the WHS syndrome.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 4 , Línea Celular , Mapeo Cromosómico , Eliminación de Gen , Trastornos del Crecimiento/genética , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Microcefalia/genética , SíndromeRESUMEN
Controversy persists concerning the significance of Huntington disease (HD) alleles in the 36-39 repeat range. Although some clinically affected persons have been documented with repeats in this range, elderly unaffected individuals have also been reported. We examined 10 paternal transmissions of HD alleles of 37-39 repeats in collateral branches of families with de novo HD. All 10 descendants, including many who are elderly, are without symptoms of HD. Forty percent of the transmissions were unstable, although none varied by more than one repeat. The observation that individuals with alleles of 37-39 repeats may survive unaffected beyond common life expectancy supports the presence of reduced penetrance for HD among some persons with repeat sizes which overlap the clinical range. Non-penetrance may be increased in the collateral branches of de novo mutation families when compared to penetrance estimates from patient series. There was no CAA-->CAG mutation for the penultimate glutamine in either a de novo expanded 42 repeat allele or the corresponding non-penetrant 38 repeat allele in a family with fresh mutation to HD.
Asunto(s)
Enfermedad de Huntington/genética , Mutación , Secuencias Repetitivas de Ácidos Nucleicos , Adulto , Anciano , Anciano de 80 o más Años , Frecuencia de los Genes , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Análisis de Secuencia de ADN , Repeticiones de TrinucleótidosRESUMEN
We recently cloned genomic sequences containing the promoter region for the messenger RNA cap binding protein (eIF4E). As the rate-limiting step in translation, eukaryotic initiation factor 4E is important in cellular growth control. Using oligonucleotide primers specific for the promoter region in polymerase chain reactions (PCR), we amplified the human gene in a chromosome 4-specific human/rodent somatic cell panel. This panel mapped single copy genomic sequences for eIF4E in the region 4q21 to 4q25.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 4/química , Genes , Factores de Iniciación de Péptidos/genética , Animales , Cricetinae , Factor 4E Eucariótico de Iniciación , Humanos , Células HíbridasRESUMEN
Fibroblast growth factor receptor 3 (FGFR3) is a developmentally regulated transmembrane protein. Three other FGFRs (1, 2, and 4) in conjunction with FGFR3 are part of the receptor tyrosine kinase super-family. Mutations in three of these genes (FGFR1, 2, and 3) have been determined to be the cause of human growth and developmental disorders. We have characterized a 22-kb DNA fragment containing the human FGFR3 gene and determined 11 kb of its nucleotide sequence. The gene consists of 19 exons and 18 introns spanning 16.5 kb, and the boundaries between exons and introns follow the GT/AG rule. The translation initiation and termination sites are located in exon 2 and exon 19 respectively. The sequence of the 5'-flanking region (1.5 kb) lacks the typical TATA or CAAT boxes. However, several putative binding sites for transcription factors SP1, AP2, Krox 24, IgHC.4, and Zeste are present. The 0.77-kb region from position -889 (5'-flanking region) to -119 (intron 1) contains a CpG island. A comparative sequence analysis of the human and mouse FGFR3 genes indicates that the overall genomic structure and organization of the human gene are nearly identical to those of its mouse counterpart. Furthermore, there is a striking similarity in the promoter regions of both genes, and several of the putative transcription factor-binding sites are conserved across species, suggesting a definitive role of these factors in the transcriptional regulation of these genes.
Asunto(s)
Proteínas Tirosina Quinasas , Receptores de Factores de Crecimiento de Fibroblastos/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión/genética , Secuencia Conservada , Islas de CpG , ADN/genética , ADN/metabolismo , Exones , Humanos , Intrones , Ratones , Datos de Secuencia Molecular , Estructura Molecular , Regiones Promotoras Genéticas , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Receptores de Factores de Crecimiento de Fibroblastos/química , Mapeo Restrictivo , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Especificidad de la Especie , Factores de Transcripción/metabolismoRESUMEN
Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome characterised by mental and developmental defects resulting from the absence of a segment of one chromosome 4 short arm (4p16.3). Due to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to identify genes that contribute to human development and whose absence results in this syndrome, we have utilised a series of landmark cosmids to characterise a collection of WHS patient derived cell lines. Fluorescence in situ hybridisation with these cosmids was used to refine the WHS critical region (WHSCR) to 260 kb. The genomic sequence of this region is available and analysis of this sequence through BLAST detected several cDNA clones in the dbEST data base. A total of nine independent cDNAs, and their predicted translation products, from this analysis show no significant similarity to members of DNA or protein databases. Furthermore, these genes have been localised within the WHS critical region and reveal an interesting pattern of transcriptional organisation. A previously published report of a patient with proximal 4p- syndrome further refines the WHSCR to 165 kb defined by the loci D4S166 and D4S3327. This work provides the starting point to understand how multiple genes or other mechanisms can contribute to the complex phenotype associated with the Wolf-Hirschhorn syndrome.
Asunto(s)
Anomalías Múltiples/genética , Mapeo Cromosómico , Cromosomas Humanos Par 4 , Secuencia de Bases , Línea Celular , ADN Complementario , Eliminación de Gen , Humanos , Datos de Secuencia Molecular , SíndromeRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tandem array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are also present in other locations in the human genome, including the short arms of all the acrocentric chromosomes. Here, we examine two models for the role of this repeat in FSHD. First, because of the extensive similarity between the 3.2 kb repeats on 4q and those adjacent to rDNA on the acrocentric chromosomes, we investigated whether the FSHD region on 4q is involved in sub-nuclear localization, specifically to the nucleolus. The results likely exclude any involvement of nucleolar localization in the development of FSHD. Second, we investigated a model that suggests that a functional gene may be buried within the tandem array of 3.2 kb repeats. Toward this end, we evaluated the evolutionary conservation of the repeat and a double homeodomain sequence within the repeat in a variety of primate species. The genomic organization of the 3.2 kb repeat in humans, great apes and lower primates identified the FSHD-associated repeat on chromosome 4q as the likely ancestral copy. The sequence of the rhesus monkey double homeodomain reveals significant sequence identity with the human 4q sequence. These results strongly suggest a functional role for a component of the FSHD-associated repeat.
Asunto(s)
Genes Homeobox , Modelos Biológicos , Distrofias Musculares/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Evolución Molecular , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
The type II cGMP-dependent protein kinase is an enzyme originally isolated from the small intestine, and is thought to be involved in the regulation of intestinal ion transport and fluid secretion. A complementary DNA clone encoding a part of the human type II cGMP-dependent protein kinase was isolated from a cerebellum library. Based on sequence information from this complementary DNA, the 5'-end of the type II cGMP-dependent protein kinase was amplified from human brain messenger RNA using polymerase chain reaction. The composite complementary DNA encoded a 762 amino acid protein with a calculated molecular mass of 87.4 kDa. Messenger RNAs encoding the type II cGMP-dependent protein kinase were detected in small intestine, colon and prostate. By using polymerase chain reaction and Southern blotting on somatic cell hybrids, the gene encoding, the type II cGMP-dependent protein kinase was mapped to human chromosome 4q13.1-q21.1.
Asunto(s)
Cerebelo/enzimología , Cromosomas Humanos Par 4 , Proteínas Quinasas Dependientes de GMP Cíclico/biosíntesis , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , Clonación Molecular , Colon/enzimología , Cartilla de ADN , ADN Complementario , Femenino , Biblioteca de Genes , Humanos , Células Híbridas , Intestino Delgado/enzimología , Isoenzimas/biosíntesis , Isoenzimas/genética , Masculino , Ratones , Datos de Secuencia Molecular , Especificidad de Órganos , Ovario/enzimología , Reacción en Cadena de la Polimerasa , Próstata/enzimología , ARN Mensajero/análisis , ARN Mensajero/biosíntesisRESUMEN
The fibroblast growth factor receptor 3 (Fgfr3) protein is a tyrosine kinase receptor involved in the signal transduction of various fibroblast growth factors. Recent studies suggest its important role in normal development. In humans, mutation in Fgfr3 is responsible for growth disorders such as achondroplasia, hypoachondroplasia, and thanatophoric dysplasia. Here, we report the complete genomic organization of the mouse Fgfr3 gene. The murine gene spans approximately 15 kb and consists of 19 exons and 18 introns. One major and one minor transcription initiation site were identified. Position +1 is located 614 nucleotides upstream from the ATG initiation codon. The translation initiation and termination sites are located in exons 2 and 19, respectively. Five Sp1 sites, two AP2 sites, one Zeste site, and one Krox 24 site were observed in the 5'-flanking region. The Fgfr3 promoter appears to be contained within a CpG island and, as is common in genes having multiple Sp1-binding sites, lacks a TATA box.
Asunto(s)
Factores de Crecimiento de Fibroblastos/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Animales , Secuencia de Bases , ADN Complementario , Exones , Factor 3 de Crecimiento de Fibroblastos , Intrones , Ratones , Datos de Secuencia MolecularRESUMEN
Dentinogenesis imperfecta type II (DGI-II) is an autosomal dominant disorder of dentin formation, which has previously been mapped to chromosome 4q12-21. In the current study, six novel short tandem-repeat polymorphisms (STRPs) have been isolated, five of which show significant evidence of linkage to DGI-II. To determine the order of the STRPs and define the genetic distance between them, nine loci (including polymorphisms for two known genes) were mapped through the CEPH reference pedigrees. The resulting genetic map encompasses 16.3 cM on the sex-averaged map. To combine this map with a physical map of the region, all of the STRPs were mapped through a somatic cell hybrid panel. The most likely location for the DGI-II locus within the fixed marker map is in the D4S2691-D4S2692 interval of 6.6 cM. The presence of a marker that shows no recombination with the DGI-II phenotype between the flanking markers provides an important anchor point for the creation of physical continuity across the DGI-II candidate region.