High incidence of the R276X SALL1 mutation in sporadic but not familial Townes-Brocks syndrome and report of the first familial case

Kohlhase, Jiirgen; Liebers, Manuela; Backe, J.; Baumann-Muller, A; Bembea, Marius; Destrée, Anne; Gattas, Michael; Grussner, S; Müller, Thomas; Mortier, Geert; Skrypnyk, Cristina; Yano, Shoji; Wirbelauer, Johannes; Michaelis, Rc

doi:10.1136/jmg.40.11.e127

Cited by 26 publications

(28 citation statements)

References 14 publications

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“…To date, most of SALL1 gene mutations reported reside in exon 2, in particular, 5′ to or within the region encoding the first double zinc finger [8][9][10][11][13][14][15]. Among them, the mutation 826 C N T in a CG dimmer identified by several research groups revealed the existence of a mutation hot spot [8,10,11]. Therefore, it is predicted that mutations lead to a preterminal stop codon and produce a truncated SALL1 protein lacking all 4 double zinc finger domains [9,10].…”

Section: Discussionmentioning

confidence: 96%

“…A single C2H2 motif is attached to the second domain and a C2HC motif at the amino terminus [9,12]. To date, most of SALL1 gene mutations reported reside in exon 2, in particular, 5′ to or within the region encoding the first double zinc finger [8][9][10][11][13][14][15]. Among them, the mutation 826 C N T in a CG dimmer identified by several research groups revealed the existence of a mutation hot spot [8,10,11].…”

Section: Discussionmentioning

confidence: 97%

“…Besides the anorectal, limb, and ear anomalies, further malformations are composed of renal, genitourinary, cardiac abnormalities and mental retardation, including renal hypoplasia/dysplasia, ureterovesical reflux, meatal stenosis, truncus arteriosus, pulmonary valve atresia, and tetralogy of Fallot [2][3][4][5][6][7][8]. Thus, the clinical manifestations of Townes-Brocks syndrome (TBS [MIM# 23107480]) are highly variable.…”

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confidence: 99%

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Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature

Liang¹,

Shen²,

Cai³

2008

Journal of Pediatric Surgery

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

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confidence: 99%

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Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature

Liang¹,

Shen²,

Cai³

2008

Journal of Pediatric Surgery

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“…An increase in the clinical severity has been observed in a number of families with TBS, frequently in patients that inherited the disease from their mothers. 3,6,8,9,12,13 Anticipation is common in trinucleotide repeat disorders such as Huntington's disease and myotonic dystrophy where a dynamic mutation in DNA occurs. However, increased severity in TBS cannot be explained genetically, as triplet repeat disease.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic variability in a family with Townes–Brocks syndrome

et al. 2010

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Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterized by external ear anomalies with sensorineural hearing loss, limb anomalies, renal and anorectal malformations. TBS is caused by mutations in SALL1, a gene mapped to chromosome 16q12.1. We report three generations of a family with SALL1 c.1326delC (p.Ser442fs) mutation, showing increased clinical severity over generations. The members of the first generation demonstrated polydactyly and deafness. In the second generation, the mother and uncle of the proband additionally had renal and/or anal anomalies. The proband in the third generation showed the most severe symptoms including congenital heart disease. Increase in clinical severity in successive generations in TBS cannot be explained genetically. There is wide clinical variation in TBS; however, most affected parents are usually mildly affected and may have similarly or more severely affected children. Social and/or physical bias at reproduction may contribute to an apparent increase in clinical severity over generations in TBS.

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“…It is caused by mutations in the putative zinc finger transcription factor gene SALL1 (Kohlhase et al, 1998). All disease-causing mutations reported from TBS patients to date are resulting in premature termination codons (Albrecht et al, 2004;Devriendt et al, 2002;Engels et al, 2000;Kohlhase, 2000;Kohlhase et al, 2003). Initially, based on this observation and the association of TBS with structural chromosomal anomalies i.e.…”

Section: Introductionmentioning

confidence: 99%

Detection of heterozygousSALL1 deletions by quantitative real time PCR proves the contribution of aSALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome

et al. 2006

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Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited disordercharacterized 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 heteronor 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.

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High incidence of the R276X SALL1 mutation in sporadic but not familial Townes-Brocks syndrome and report of the first familial case

Cited by 26 publications

References 14 publications

Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature

Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature

Phenotypic variability in a family with Townes–Brocks syndrome

Detection of heterozygousSALL1 deletions by quantitative real time PCR proves the contribution of aSALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome

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