Townes‐Brocks syndrome: Detection of a SALL1 mutation hot spot and evidence for a position effect in one patient

University of Ferrara, Ferrare, Emilia-Romagna, Italy
Human Mutation (Impact Factor: 5.14). 11/1999; 14(5):377 - 386. DOI: 10.1002/(SICI)1098-1004(199911)14:5<377::AID-HUMU3>3.0.CO;2-A


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.

Download full-text


Available from: Rima Slim, Nov 20, 2015
  • Source
    • "It shows similar expression in humans and mice and is thought to be a developmental regulator in humans during organogenesis in weeks 5 to 10. However, detection rates of SALL1 mutations are variable (64% and 83% in 2 different studies) because of diagnostic overlap with other conditions [18] [19]. Despite the difficulty in ascribing a single syndrome to explain the anomalies, this boy displays features that may represent the concurrence of a number of factors—genetic predisposition, vascular compromise, and unidentified external drugs—that can that can affect multiple systems in the developing fetus. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This is a case report of a child with a rare combination of pyloric and colonic atresias, imperforate anus, hypoganglionosis of the rectum and sigmoid colon, unilateral multicystic dysplastic kidney, bilateral sensorineural deafness, spondyloepimetaphyseal dysplasia, subglottic stenosis, growth failure, and limb anomalies.
    Full-text · Article · Dec 2011 · Journal of Pediatric Surgery
  • Source
    • "Since the expression pattern of Sall1 is conserved in tetrapods, an enhancer screen should concentrate on this 1.5 Mbp region and include the introns of a flanking gene. Two additional lines of evidence that support this hypothesis are shown: a) Chromosomal breakage of a major part of the non-coding region has the same effect as a mutation in the gene SALL1 (Marlin et al., 1999). b) Several conserved non-coding sequences in this region were tested in mice and direct an expression pattern reminiscent of SALL1 (Pennacchio et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A major prerequisite for the investigation of tissue-specific processes is the identification of cis-regulatory elements. No generally applicable technique is available to distinguish them from any other type of genomic non-coding sequence. Therefore, researchers often have to identify these elements by elaborate in vivo screens, testing individual regions until the right one is found. Here, based on many examples from the literature, we summarize how functional enhancers have been isolated from other elements in the genome and how they have been characterized in transgenic animals. Covering computational and experimental studies, we provide an overview of the global properties of cis-regulatory elements, like their specific interactions with promoters and target gene distances. We describe conserved non-coding elements (CNEs) and their internal structure, nucleotide composition, binding site clustering and overlap, with a special focus on developmental enhancers. Conflicting data and unresolved questions on the nature of these elements are highlighted. Our comprehensive overview of the experimental shortcuts that have been found in the different model organism communities and the new field of high-throughput assays should help during the preparation phase of a screen for enhancers. The review is accompanied by a list of general guidelines for such a project.
    Full-text · Article · Feb 2011 · Developmental Biology
  • Source
    • "Absence of PTEN can also alter ESC properties and impair kidney development [33]–[35]. SALL1 is a stem cell factor in kidney development [36], and is mutated in patients with Townes-Brocks syndrome (TBS), whose features include renal malformations [37]–[39]. Genetic targeting of mouse SALL1 results in severe renal dysplasia or complete agenesis, indicating that SALL1 plays an essential role in early kidney development. In addition, SALL1 is expressed in both human and mouse ESCs, and has been associated with a potential role in leukemogenesis [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The embryonic stem cell (ESC) factor, SALL4, plays an essential role in both development and leukemogenesis. It is a unique gene that is involved in self-renewal in ESC and leukemic stem cell (LSC). To understand the mechanism(s) of SALL4 function(s), we sought to identify SALL4-associated proteins by tandem mass spectrometry. Components of a transcription repressor Mi-2/Nucleosome Remodeling and Deacetylase (NuRD) complex were found in the SALL4-immunocomplexes with histone deacetylase (HDAC) activity in ESCs with endogenous SALL4 expression and 293T cells overexpressing SALL4. The SALL4-mediated transcriptional regulation was tested on two potential target genes: PTEN and SALL1. Both genes were confirmed as SALL4 downstream targets by chromatin-immunoprecipitation, and their expression levels, when tested by quantitative reverse transcription polymerase chain reaction (qRT-PCR), were decreased in 293T cells overexpressing SALL4. Moreover, SALL4 binding sites at the promoter regions of PTEN and SALL1 were co-occupied by NuRD components, suggesting that SALL4 represses the transcriptions of PTEN and SALL1 through its interactions with the Mi-2/NuRD complex. The in vivo repressive effect(s) of SALL4 were evaluated in SALL4 transgenic mice, where decreased expressions of PTEN and SALL1 were associated with myeloid leukemia and cystic kidneys, respectively. In summary, we are the first to demonstrate that stem cell protein SALL4 represses its target genes, PTEN and SALL1, through the epigenetic repressor Mi-2/NuRD complex. Our novel finding provides insight into the mechanism(s) of SALL4 functions in kidney development and leukemogenesis.
    Full-text · Article · Feb 2009 · PLoS ONE
Show more