RESUMO
The genes for human and mouse Suppressor of Fused (SU(FU)/Su(Fu)) in the Hedgehog signaling pathway were characterized and found to contain 12 exons. Human SU(FU) localized on chromosome 10q24-25 between the markers D10S192 and AFM183XB12. We detected three additional SU(FU) isoforms, two of which have lost their ability to interact with the transcription factor GLI1. Expression analysis using whole mount in situ hybridization revealed strong expression of Su(Fu) in various mouse embryonic tissues. SU(FU) was considered a candidate gene for the split-hand/split-foot malformation type 3 (SHFM3). However, no alterations in the SU(FU) gene were found in SHFM3 patients.
Assuntos
Cromossomos Humanos Par 10 , Deformidades Congênitas do Pé/genética , Regulação da Expressão Gênica no Desenvolvimento , Deformidades Congênitas da Mão/genética , Proteínas Repressoras/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Marcadores Genéticos , Humanos , Hibridização In Situ , Camundongos , Camundongos Endogâmicos , Dados de Sequência Molecular , Mutação , Splicing de RNA , Proteínas Repressoras/metabolismoRESUMO
We identified a family with three males in two generations with moderate mental retardation. The two oldest were first cousins whose mothers were sisters. The third affected was a grandson through a daughter of one of the sisters, strongly suggesting X- linked inheritance. The affected males had prominent glabella, synophrys, prognathism, generalized hirsutism, and bilateral single palmar creases. All developed seizures in childhood. The two oldest have had a slow deterioration in neurological status with poor gait and balance and progressive weakness. No deterioration in their mental status has been observed. The oldest had cerebellar atrophy confirmed on computed tomography and magnetic resonance imaging scans of the brain and prolonged nerve conduction velocity. Two of the males had hypogammaglobulinemia (IgA deficient). Two-point linkage analysis using 27 microsatellite markers on the X chromosome resulted in a maximum LOD score of 2.23 at straight theta = 0 for locus DSX101. Recombination was observed at locus DSX1170 in Xq21.33 and locus DXS8067 in Xq23. We conclude that this family represents an X-linked disorder associated with a recognizable phenotype, progressive neurological deterioration, and variable hypogammaglobulinemia. The gene appears to lie between Xq21.33 and Xq23.
Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Cromossomo X/genética , Adulto , Agamaglobulinemia , Mapeamento Cromossômico , DNA/genética , Saúde da Família , Feminino , Marcha , Ligação Genética , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Convulsões , SíndromeRESUMO
FG syndrome is a rare X-linked recessive form of mental retardation, first described by Opitz and Kaveggia in 1974 in five related males with mental retardation, disproportionately large heads, imperforate anus, and congenital hypotonia. Partial agenesis of the corpus callosum was noted in at least one of the initial cases and has been seen in a number of subsequently-reported cases. The associated congenital hypotonia with joint hyperlaxity tends to progress to contractures with spasticity and unsteady gait in later life. The presence of subtle facial abnormalities and the characteristic behavior in midchildhood facilitate diagnosis at this age, particularly when there are other affected male relatives in the maternal family. Recently, Briault et al. [1997] mapped a gene for FG syndrome to the Xq12-q21.31 region. We describe three additional families (six additional patients) with FG syndrome on whom we have conducted linkage analysis. Our findings support the localization of a gene for the FG syndrome in Xq12-q21. In addition, we have noted skewed X-inactivation in carrier females, as well as new associated findings in affected males of sagittal craniosynostosis and split hand malformation.
Assuntos
Anormalidades Múltiplas/genética , Ligação Genética , Deficiência Intelectual/genética , Cromossomo X , Mecanismo Genético de Compensação de Dose , Fácies , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , SíndromeAssuntos
Heterozigoto , Defeitos do Tubo Neural/genética , Oxirredutases/genética , Aborto Espontâneo/genética , Alelos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Homozigoto , Humanos , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NAD+) , Mutação/genética , Defeitos do Tubo Neural/enzimologia , Gravidez , Fatores Sexuais , Disrafismo Espinal/enzimologia , Disrafismo Espinal/genéticaRESUMO
The split hand-split foot (SHSF) malformation affects the central rays of the upper and lower limbs. It presents either as an isolated defect or in association with other skeletal or non-skeletal abnormalities. An autosomal SHSF locus (SHFM1) was previously mapped to 7q22.1. We report the mapping of a second autosomal SHSF locus to 10q24-->25. A panel of families was tested with 17 marker loci mapped to the 10q24-->25 region. Maximum lod scores of 3.73, 4.33 and 4.33 at a recombination fraction of zero were obtained for the loci D10S198, PAX2 and D10S1239, respectively. An 19 cM critical region could be defined by haplotype analysis and several genes with a potential role in limb morphogenesis are located in this region. Heterogeneity testing indicates the existence of at least one additional autosomal SHSF locus.
