Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present clinical findings and molecular characterization in two patients previously diagnosed as 46,XY female gonadal dysgenesis with germ cell tumour. Both patients showed a female general phenotype with unambiguously female external genitalia and primary amenorrhoea compatible with complete androgen insensitivity syndrome. The first patient, at the age of 31 years, developed a dysgerminoma measuring 8 x 13 x 10 cm in one abdominal testis. Genetic analysis revealed a single nucleotide substitution on exon 4 in the hormone-binding domain of the androgen receptor (AR) gene, resulting in a change of codon 681 GAG (glutamic acid) to AAG (lysine). The second patient, at the age of 17 years, developed a dysgerminoma measuring 12 x 10 x 7 cm in one abdominal testis and gonadoblastoma in the other testis. Genetic analysis showed a point mutation on exon 3 in the DNA-binding domain of the AR gene resulting in a change of codon 607 CGA (arginine) to CAA (glutamine). Arg607-Gln and Arg608-Lys point mutations in the DNA-binding domain of the AR gene have been associated with male breast cancer in partial androgen insensitivity syndrome. A codon 607 mutation in the DNA-binding domain of the AR gene in our patient 2 is associated with early development of germ cell tumour. We suggest regular molecular genetic analysis of the AR gene in 46,XY females with germ cell tumour and androgen insensitivity syndrome to detect differences in the specific regions of AR gene involved in early progression toward oncogenesis of the dysgenetic gonads.
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PMID:Androgen receptor gene mutations in 46,XY females with germ cell tumours. 1022 92

FOXP2 is a transcription factor containing a polyglutamine tract, a zinc-finger motif, and a forkhead DNA-binding domain. The FOXP2 gene is located on 7q31. A missense mutation in the forkhead domain (exon 14) and a balanced reciprocal translocation t(5;7)(q22;q31.2) with a breakpoint between exons 3b and 4 have recently been associated with a speech and language disorder (SPCH1). The role of FOXP2 in this neurodevelopmental disorder suggests that mutations in FOXP2 could cause other neuropsychiatric disorders. To begin investigation of this possibility, we examined the genomic structure and CAG/CAA repeat region of FOXP2. We detected little polymorphism and no expansions in the FOXP2 CAG/CAA repeat in 142 individuals with progressive movement disorders. We found evidence of alternate splice variants and six previously undetected exons: three 5' untranslated exons (s1, s2, s3), two additional untranslated exons (2a and 2b) between exons 2 and 3, a translated exon (4a) between exons 4 and 5, and a longer version of exon 10 (10+) that contains an alternate stop codon and produces a truncated protein (FOXP2-S). Our results suggest that FOXP2 spans at least 603 kb of genomic DNA, more than twice the previously defined region, and provide evidence of a promoter region flanking exon s1. This demonstration of additional FOXP2 exons and splice variants should facilitate understanding of FOXP2 function and the search for additional FOXP2 mutations.
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PMID:FOXP2: novel exons, splice variants, and CAG repeat length stability. 1218 86

Several ectodermal dysplasia syndromes have been shown to result from mutations in the gene that encodes the transcription factor p63. We describe an 11-year-old boy, with clinically normal parents, who had a developmental disorder that resembled EEC (ectrodactyly ectodermal dysplasia-clefting) syndrome (OMIM 604292). He had ectrodactyly and missing middle fingers bilaterally, onychodysplasia, hypodontia with missing teeth, hypohidrosis and lacrimal duct obstruction. DNA sequencing disclosed a heterozygous G-->A substitution at nucleotide 893, that converts an arginine residue (CGA) to glutamine (CAA), the mutation being designated R298Q. This mutation occurs within the DNA-binding domain of p63, and is close to many of the published EEC syndrome mutations. However, R298Q has been described once previously in a large German pedigree, not with EEC syndrome, but another ectodermal dysplasia disorder, ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome (OMIM 103285). Further clinical assessment in our patient revealed that, apart from not having cleft lip and/or palate, he had an exfoliative dermatitis of his hands and feet, and some freckling on his face and shoulders. Collectively, these features support a diagnosis of ADULT syndrome. This study has identified a specific genotype-phenotype correlation in a rare ectodermal dysplasia syndrome and the findings are useful in improving genetic counselling in this family.
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PMID:ADULT ectodermal dysplasia syndrome resulting from the missense mutation R298Q in the p63 gene. 1555 Jan 49

Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence-binding protein (ICSBP) is a transcription factor that controls myeloid-cell development. Microarray gene expression analysis of Irf-8-/- myeloid progenitor cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8-induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation.
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PMID:Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages. 1594 94

The FsrABDC signal transduction system is a major virulence regulator in Enterococcus faecalis. The FsrC sensor histidine kinase, upon activation by the gelatinase biosynthesis-activating pheromone (GBAP) peptide encoded by the fsrBD genes, phosphorylates the FsrA response regulator required for the transcription of the fsrBDC and the gelE-sprE genes from the fsrB promoter and the gelE promoter, respectively. FsrA belongs to the LytTR family of proteins, which includes other virulence regulators, such as AgrA of Staphylococcus aureus, AlgR of Pseudomonas aeruginosa, and VirR of Clostridium perfringens. The LytTR DNA-binding domain that characterizes these proteins generally binds to two imperfect direct repeats separated by a number of bases that place the repeats on the same face of the DNA helix. In this study, we demonstrated that FsrA also binds to two imperfect direct repeats separated by 13 bp, based on the consensus sequence of FsrA, T/AT/CAA/GGGAA/G, which is consistent with the binding characteristics of LytTR domains.
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PMID:Enterococcus faecalis virulence regulator FsrA binding to target promoters. 2125 71