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Jürgen Kohlhase - One of the best experts on this subject based on the ideXlab platform.

  • Kidney failure in Townes-Brocks Syndrome: an under recognized phenomenon?
    American Journal of Medical Genetics Part A, 2007
    Co-Authors: William Reardon, Liam F. Casserly, Ralf Birkenhäger, Jürgen Kohlhase
    Abstract:

    Though uncommon, kidney malformations are described in several cases of Townes-Brocks Syndrome. By contrast, kidney failure has been reported as the presenting feature of Townes-Brocks Syndrome on only one occasion. While the SALL1 gene, mutations of which result in the Townes-Brocks phenotype, is expressed in the developing kidney, the absence of other corroborative reports of kidney failure presenting in affected individuals suggests that the solitary observation of kidney failure is as likely due to chance as to causal association. In now reporting a further instance of this association, we review the literature, demonstrating that several other instances of kidney failure are in fact known, despite an incomplete dataset. These findings suggest that kidney failure may be a constituent element of the natural history of Townes-Brocks Syndrome and raise the possible benefits of longitudinal survey for progressive kidney impairment in patients with this Syndrome.

  • SALL1 mutations in sporadic Townes-Brocks Syndrome are of predominantly paternal origin without obvious paternal age effect.
    American journal of medical genetics. Part A, 2006
    Co-Authors: Johann Böhm, Susanne Munk-schulenburg, Stephanie Felscher, Jürgen Kohlhase
    Abstract:

    Autosomal dominant Townes–Brocks Syndrome (TBS) is characterized by imperforate anus, triphalangeal and supernumerary thumbs, dysplastic ears and sensorineural hearing loss, and may also involve other organ systems. Strong inter- and intrafamiliar variability is known. Approximately 50% of TBS cases are sporadic and due to de novo mutations in the SALL1 gene. SALL1 encodes a zinc finger protein operating as a transcriptional repressor and localizing to pericentromeric heterochromatin. We traced the parental origin of SALL1 mutations in sporadic TBS by analysis of linkage between SALL1 mutations and exonic or intronic polymorphisms in 16 families with 10 different mutations. Mutations were of paternal origin in 14 of 16 cases (87.5%). Paternal origin was independent of the mutation type. The mean paternal age at conception was 29.9 and the mean maternal age 26.5 years. We conclude that de novo mutations in SALL1 mostly occur on the paternally derived chromosome 16 without an obvious age effect. © 2006 Wiley-Liss, Inc.

  • Defining the heterochromatin localization and repression domains of SALL1.
    Biochimica et biophysica acta, 2006
    Co-Authors: Christian Netzer, Stefan K. Bohlander, Markus Hinzke, Ying Chen, Jürgen Kohlhase
    Abstract:

    Abstract SALL1 has been identified as one of four human homologues of the Drosophila region-specific homeotic gene spalt (sal), encoding zinc finger proteins of characteristic structure. Mutations of SALL1 on chromosome 16q12.1 cause Townes–Brocks Syndrome (TBS, OMIM 107480). We have shown previously that SALL1 acts as a strong transcriptional repressor in mammalian cells when fused to a heterologous DNA-binding domain. Here, we report that SALL1 contains two repression domains, one located at the extreme N-terminus of the protein and the other in the central region. SALL1 fragments with the central repression domain exhibited a punctate nuclear distribution pattern at pericentromeric heterochromatin foci in murine NIH-3T3 cells, suggesting an association between repression and heterochromatin localization. The implications of these findings for the pathogenesis of Townes–Brocks Syndrome are discussed.

  • Detection of heterozygous SALL1 deletions by quantitative real time PCR proves the contribution of a SALL1 dosage effect in the pathogenesis of Townes-Brocks Syndrome.
    Human mutation, 2006
    Co-Authors: Wiktor Borozdin, Katharina Steinmann, Beate Albrecht, Armand Bottani, Koenraad Devriendt, Michael Leipoldt, Jürgen Kohlhase
    Abstract:

    Townes-Brocks Syndrome (TBS) is an autosomal dominantly inherited disorder characterized by ear, anal, limb, and renal malformations, and results from mutations in the gene SALL1. All SALL1 mutations previously found in TBS patients create preterminal termination codons. In accordance with the findings of pericentric inversions or balanced translocations, TBS was initially assumed to be caused by SALL1 haploinsufficiency. This assumption was strongly contradicted by a Sall1 mouse knock-out, because neither hetero- nor homozygous knock-out mutants displayed a TBS-like phenotype. A different mouse mutant mimicking the human SALL1 mutations, however, showed a TBS-like phenotype in the heterozygous situation, suggesting a dominant-negative action of the mutations causing TBS. We applied quantitative real time PCR to detect and map SALL1 deletions in 240 patients with the clinical diagnosis of TBS, who were negative for SALL1 mutations. Deletions were found in three families. In the first family, a 75 kb deletion including all SALL1 exons had been inherited by two siblings from their father. A second, sporadic patient carried a de novo 1.9-2.6 Mb deletion including the whole SALL1 gene, and yet another sporadic case was found to carry an intragenic deletion of 3384 bp. In all affected persons, the TBS phenotype is rather mild as compared to the phenotype resulting from point mutations. These results confirm that SALL1 haploinsufficiency is sufficient to cause a mild TBS phenotype but suggest that it is not sufficient to cause the severe, classical form. It therefore seems that there is a different contribution of SALL1 gene function to mouse and human embryonic development.

  • expression of a truncated sall1 transcriptional repressor is responsible for Townes Brocks Syndrome birth defects
    Human Molecular Genetics, 2003
    Co-Authors: Susan M. Kiefer, Jürgen Kohlhase, Kevin K. Ohlemiller, Jing Yang, Bradley W. Mcdill, Michael Rauchman
    Abstract:

    Townes-Brocks Syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a sall1-null allele does not mimic the human Syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.

Bruce R. Korf - One of the best experts on this subject based on the ideXlab platform.

Catherine E Keegan - One of the best experts on this subject based on the ideXlab platform.

Michael Rauchman - One of the best experts on this subject based on the ideXlab platform.

  • Phenotypic and genotypic aspects of Townes-Brock Syndrome: case report of patient in southern Brazil with a new SALL1 hotspot region nonsense mutation.
    BMC medical genetics, 2017
    Co-Authors: Paulo Breno Noronha Liberalesso, Mara L. Cordeiro, Simone Karuta, Karyn Regina Jordão Koladicz, Anderson Nitsche, Bianca Simone Zeigelboim, Salmo Raskin, Michael Rauchman
    Abstract:

    Townes-Brocks Syndrome (TBS) is a rare autosomal dominant condition characterized by renal, anal, limb, and auditory abnormalities. TBS diagnosis can be challenging in settings where genetic analysis is not readily available. TBS traits overlap with those of Goldenhar and VACTERL Syndromes. Here, we present the case of a 5-year-old Brazilian boy born with an anorectal abnormality, limb and external ears malformations, genitourinary anomalies, and a congenital heart defect. Genetic analysis revealed a SALL1 nonsense mutation. The case is discussed in the context of the current literature. Because of the variability in TBS clinical presentation, genetic analysis is key to the differential diagnosis of TBS relative to phenotypically similar Syndromes.

  • SALL1 truncated protein expression in Townes-Brocks Syndrome leads to ectopic expression of downstream genes.
    Human mutation, 2008
    Co-Authors: Susan M. Kiefer, Lynn Robbins, Andrew R. Barina, Zhihong Zhang, Michael Rauchman
    Abstract:

    Mutations in SALL1 lead to the dominant multiorgan congenital anomalies that define Townes-Brocks Syndrome (TBS). The majority of these mutations result in premature termination codons that would be predicted to trigger nonsense-mediated decay (NMD) of mutant mRNA and cause haploinsufficiency. Our previous studies using a gene targeted mouse model (Sall1-DeltaZn) suggested that TBS phenotypes are due to expression of a truncated mutant protein, not haploinsufficiency. In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients. We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient. TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb. We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall-responsive target genes.

  • expression of a truncated sall1 transcriptional repressor is responsible for Townes Brocks Syndrome birth defects
    Human Molecular Genetics, 2003
    Co-Authors: Susan M. Kiefer, Jürgen Kohlhase, Kevin K. Ohlemiller, Jing Yang, Bradley W. Mcdill, Michael Rauchman
    Abstract:

    Townes-Brocks Syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a sall1-null allele does not mimic the human Syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.

  • Expression of a truncated Sall1 transcriptional repressor is responsible for Townes–Brocks Syndrome birth defects
    Human molecular genetics, 2003
    Co-Authors: Susan M. Kiefer, Jürgen Kohlhase, Kevin K. Ohlemiller, Jing Yang, Bradley W. Mcdill, Michael Rauchman
    Abstract:

    Townes-Brocks Syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a sall1-null allele does not mimic the human Syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.

John B Mulliken - One of the best experts on this subject based on the ideXlab platform.