RESUMEN
Deletions in the heparan sulphate proteoglycan encoding glypican 3 (GPC3) gene have recently been documented in several Simpson-Golabi-Behmel syndrome (SGBS) families. However, no precisely defined SGBS mutation has been published. We report here a 13 base pair deletion which causes a frameshift and premature termination of the GPC3 gene in the Dutch-Canadian SGBS family in whom the trait was originally mapped. Our analysis shows that a discrete GPC3 disabling mutation is sufficient to cause SGBS. Furthermore, our finding of a GPC3 normal daughter of an SGBS carrier with skeletal abnormalities and Wilms tumour raises the possibility of a trans effect from the maternal carrier in SGBS kindreds.
Asunto(s)
Proteoglicanos de Heparán Sulfato , Heparitina Sulfato/genética , Proteoglicanos/genética , Eliminación de Secuencia , Huesos/anomalías , Canadá , Cromosomas Humanos Par 11/genética , Femenino , Mutación del Sistema de Lectura , Glipicanos , Heparitina Sulfato/sangre , Humanos , Masculino , Linaje , Proteoglicanos/sangre , Análisis de Secuencia de ADN , Síndrome , Tumor de Wilms/complicaciones , Cromosoma X/genéticaRESUMEN
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.
Asunto(s)
Deleción Cromosómica , Heparitina Sulfato/genética , Mutación , Proteoglicanos/genética , Anomalías Múltiples/genética , Autorradiografía , Southern Blotting , Sondas de ADN , Genotipo , Proteoglicanos de Heparán Sulfato , Humanos , Masculino , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Cromosoma X/genéticaRESUMEN
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre- and postnatal overgrowth with visceral and skeletal anomalies. To identify the causative gene, breakpoints in two female patients with X;autosome translocations were identified. The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS. GPC3 encodes a putative extracellular proteoglycan, glypican 3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed. Initial western- and ligand-blotting experiments suggest that glypican 3 forms a complex with insulin-like growth factor 2 (IGF2), and might thereby modulate IGF2 action.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas/genética , Trastornos del Crecimiento/genética , Proteoglicanos de Heparán Sulfato , Heparitina Sulfato/genética , Proteoglicanos/genética , Cromosoma X , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Trastornos de los Cromosomas , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 16 , Clonación Molecular , Cartilla de ADN , Femenino , Eliminación de Gen , Ligamiento Genético , Glipicanos , Células HeLa , Heparitina Sulfato/metabolismo , Humanos , Técnicas Inmunológicas , Factor II del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Unión Proteica , Proteoglicanos/metabolismo , Homología de Secuencia de Aminoácido , Síndrome , Translocación Genética , Células Tumorales CultivadasRESUMEN
Simpson-Golabi-Behmel (SGB) syndrome is an X-linked condition with pre- and postnatal overgrowth, characteristic facies, and visceral and skeletal anomalies. We report an affected male who presented at 16 weeks' gestation with elevated maternal serum alpha-fetoprotein (MSAFP). Fetal measurements at 20 and 31 weeks' gestation were disproportionate, with marked macrosomia but a low head to abdominal circumference ratio and normal femur length. Fetal overgrowth with elevated MSAFP may prove to be useful markers for the prenatal diagnosis of SGB syndrome.
Asunto(s)
Anomalías Múltiples/genética , Macrosomía Fetal/genética , Trastornos del Crecimiento/genética , alfa-Fetoproteínas/metabolismo , Adulto , Antropometría , Femenino , Ligamiento Genético , Humanos , Masculino , Embarazo , Síndrome , Cromosoma X , alfa-Fetoproteínas/genéticaRESUMEN
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked gigantism syndrome characterized primarily by a coarse facies and somatic overgrowth which we have observed to be associated with an increased risk for embryonal tumors. Genetic linkage analysis for two SGBS kindreds in which X linked dominant inheritance was observed has been conducted for the X chromosome. The closest linkage to SGBS was observed for the Xq26 locus HPRT (Z max = 7.45, theta max = 0.00). SGBS-Xq marker recombinations map the disease locus to the DXS425-DXS1123 interval on Xq25-q27. This maps the disease locus to a region known to contain a previously characterized chromosomal translocation breakpoint found in a young girl with somatic overgrowth. This observation may have implications for the cloning of the SGBS gene.
Asunto(s)
Gigantismo/genética , Cromosoma X , Secuencia de Bases , Southern Blotting , Mapeo Cromosómico , ADN/sangre , ADN/genética , Cartilla de ADN , Femenino , Tamización de Portadores Genéticos , Ligamiento Genético , Marcadores Genéticos , Genotipo , Humanos , Hipoxantina Fosforribosiltransferasa/genética , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Recombinación Genética , Síndrome , Translocación GenéticaRESUMEN
We report 6 affected males in a 5-generation family with x-linked Simpson-Golabi-Behmel (SGB) syndrome. All had pre- and postnatal overgrowth with 2 adult males attaining heights over 195 cm. Other features included "coarse" face with hypertelorism, broad nasal root, cleft palate, full lips with a midline groove of the lower lip, grooved tongue with tongue tie, prominent mandible, congenital heart defects, arrhythmias, supernumerary nipples, splenomegaly, large dysplastic kidneys, cryptorchidism, hypospadias, skeletal abnormalities and postaxial hexadactyly. All affected individuals were of normal intelligence. One boy died at age 19 months of a neuroblastoma. The putative origin of the gene in this family was the maternal great grandmother of the propositus. Eight carrier females, who showed varying manifestations of the gene, have been identified. Anthropometric analysis has identified preliminary characteristic craniofacial dimensions in this syndrome. Molecular studies have shown a maximal lod score of 2.81 with no recombinants observed for the SGB-DXYS68 pairing, mapping the disorder to Xqcen-Xq21.3.