Townes‐Brocks syndrome: Detection of a SALL1 mutation hot spot and evidence for a position effect in one patient
ABSTRACT Townes-Brocks syndrome (TBS) is an autosomal dominant developmental disorder characterized by anal and thumb malformations and by ear anomalies that can affect the three compartments and usually lead to hearing loss. The gene underlying TBS, SALL1, is a human homolog of the Drosophila spalt gene which encodes a transcription factor. A search for SALL1 mutations undertaken in 11 unrelated affected individuals (five familial and six sporadic cases) led to the detection of mutations in nine of them. One nonsense and six different novel frameshift mutations, all located in the second exon, were identified. Together with the previously reported mutations [Kohlhase et al., 1999], they establish that TBS results from haploinsufficiency. The finding of de novo mutations in the sporadic cases is consistent with the proposed complete penetrance of the disease. Moreover, the occurrence of the same 826C>T transition in a CG dimer, in three sporadic cases from the present series and three sporadic cases from the other series [Kohlhase et al., 1999] (i.e., six of the eight mutations identified in sporadic cases), reveals the existence of a mutation hotspot. Six different SALL1 polymorphisms were identified in the course of the present study, three of which are clustered in a particular region of the gene that encodes a stretch of serine residues. Finally, the chromosome 16 breakpoint of a t(5;16)(p15.3;q12.1) translocation carried by a TBS-affected individual was mapped at least 180 kb telomeric to SALL1, thus indicating that a position effect underlies the disease in this individual. Hum Mutat 14:377–386, 1999. © 1999 Wiley-Liss, Inc.
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ABSTRACT: Several single nucleotide polymorphisms (SNPs) and the Rep-1 microsatellite marker of the α-synuclein ( SNCA) gene have consistently been shown to be associated with Parkinson’s disease, but the functional relevance is unclear. Based on these findings we hypothesized that conserved cis-regulatory elements in the SNCA genomic region regulate expression of SNCA, and that SNPs in these regions could be functionally modulating the expression of SNCA, thus contributing to neuronal demise and predisposing to Parkinson’s disease. In a pair-wise comparison of a 206kb genomic region encompassing the SNCA gene, we revealed 34 evolutionary conserved DNA sequences between human and mouse. All elements were cloned into reporter vectors and assessed for expression modulation in dual luciferase reporter assays. We found that 12 out of 34 elements exhibited either an enhancement or reduction of the expression of the reporter gene. Three elements upstream of the SNCA gene displayed an approximately 1.5 fold (p<0.009) increase in expression. Of the intronic regions, three showed a 1.5 fold increase and two others indicated a 2 and 2.5 fold increase in expression (p<0.002). Three elements downstream of the SNCA gene showed 1.5 fold and 2.5 fold increase (p<0.0009). One element downstream of SNCA had a reduced expression of the reporter gene of 0.35 fold (p<0.0009) of normal activity. Our results demonstrate that the SNCA gene contains cis-regulatory regions that might regulate the transcription and expression of SNCA. Further studies in disease-relevant tissue types will be important to understand the functional impact of regulatory regions and specific Parkinson’s disease-associated SNPs and its function in the disease process.12/2014; 3(259). DOI:10.12688/f1000research.3281.2
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ABSTRACT: Townes-Brocks syndrome (TBS) is a rare autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator sal of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved C2H2 double zinc finger domains which are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Nineteen out of 20 SALL1 mutations known to date are located in exon 2, 5′ of the third double zinc finger encoding region. These are nonsense mutations, short insertions, and short deletions, as well as one gross intraexonic deletion. One mutation within intron 2 creates an aberrant splice site. Most mutations lead to preterminal stop codons and are thought to cause the phenotype via haploinsufficiency. However, one short deletion results in a phenotype different from TBS which might be due to a dominant negative effect of a truncated SALL1 protein. Hum Mutat 16:460–466, 2000. © 2000 Wiley-Liss, Inc.Human Mutation 11/2000; 16(6):460 - 466. DOI:10.1002/1098-1004(200012)16:6<460::AID-HUMU2>3.0.CO;2-4 · 5.05 Impact Factor
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ABSTRACT: Pierre Robin sequence (PRS) consists of the nonrandom association of micrognathia, cleft palate (CP), and glossoptosis. It also includes respiratory and feeding difficulties that appear to be neurogenic rather than mechanical in causation. Genetic determinants are thought to underlie this functional and morphological entity, based on the existence of Mendelian syndromes with PRS, and the rare observations of familial nonsyndromic PRS, in which some of the affected individuals have isolated CP. We report the association of PRS with deletion 2q32.3-q33.2 due to an unbalanced reciprocal translocation 46,XX, t(2;21), del 2(q32.3q33.2), and we refine the deletion interval with regard to YAC probes and polymorphic DNA markers. The deletion was shown to be flanked by D2S369 (telomeric) and D2S315 (centromeric), thus it maps to a recently determined chromosomal region known to be nonrandomly associated with CP. This observation supports the hypothesis for the genetic bases of nonsyndromic PRS, strengthens its possible genetic association with isolated CP, and provides a candidate PRS locus, in chromosomal region 2q32.3-q33.2. © 2001 Wiley-Liss, Inc.American Journal of Medical Genetics 06/2001; 102(3):219 - 226. DOI:10.1002/ajmg.1448 · 3.23 Impact Factor