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Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome.

Vodopiutz J, Zoller H, Fenwick AL, Arnhold R, Schmid M, Prayer D, Müller T, Repa A, Pollak A, Aufricht C, Wilkie AO, Janecke AR - J. Pediatr. (2012)

Bottom Line: Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies.Our findings imply that quantity and quality of SALL1 transcript are important for SALL1 function and determine phenotype, and mode of inheritance, of allelic SALL1-related disorders.This novel MCA-MR emphasizes SALL1 function as critical for normal central nervous system development and warrants a detailed neurologic investigation in all individuals with SALL1 mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Austria. julia.vodopiutz@meduniwien.ac.at

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A, Simplified pedigree showing multiple consanguinity loops, CNS-TBS patients represented by filled black circles. For privacy protection carriers are not indicated. B, Sequencing chromatograms from a patient (top) and a control (bottom). The c.3160C > T mutation is indicated by an arrowhead. C, Relative quantification by pyrosequencing of the mutant versus the wild-type allele in SALL1 cDNA from carrier fibroblasts, before and after treatment by cycloheximide.
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fig2: A, Simplified pedigree showing multiple consanguinity loops, CNS-TBS patients represented by filled black circles. For privacy protection carriers are not indicated. B, Sequencing chromatograms from a patient (top) and a control (bottom). The c.3160C > T mutation is indicated by an arrowhead. C, Relative quantification by pyrosequencing of the mutant versus the wild-type allele in SALL1 cDNA from carrier fibroblasts, before and after treatment by cycloheximide.

Mentions: We delineate a novel, autosomal recessive MCA-MR, characterized by TOF, polycystic hypoplastic kidneys with prenatal onset of chronic renal failure, limb and ear malformations, sensorineural deafness, corpus callosum hypoplasia, cortical blindness, and complete lack of psychomotor development (Figure 1), already manifesting prenatally as an abnormal fetal movement pattern. Homozygosity mapping in this consanguineous family (Figure 2, A) revealed a maximal logarithm of the odds score of 1.9 within 5 homozygous intervals located on chromosomes 2, 9, and 16 (data not shown). We selected SALL1 from the largest candidate region for mutation analysis on the basis of partial clinical overlap with TBS, known function and expression patterns. Sequencing identified a homozygous SALL1 mutation, c.3160C > T (p.R1054*), in both affected siblings that segregates with the disease (Figure 2, B). Twelve healthy family members were carriers of this mutation. This novel mutation leads to a premature stop codon in exon 2 and was expected to trigger NMD. Pyrosequencing showed that the mutant transcript was present at 43% of the level of the normal transcript in carrier fibroblasts; this increased to 68% after cycloheximide treatment, indicating a partial contribution of NMD to the relative deficiency of mutant transcript (Figure 2, C). The SALL1 protein encoded by the mutant transcript lacks 270 C-terminal residues including the last double zinc finger domain and a beta-catenin binding domain (Figure 3).1


Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome.

Vodopiutz J, Zoller H, Fenwick AL, Arnhold R, Schmid M, Prayer D, Müller T, Repa A, Pollak A, Aufricht C, Wilkie AO, Janecke AR - J. Pediatr. (2012)

A, Simplified pedigree showing multiple consanguinity loops, CNS-TBS patients represented by filled black circles. For privacy protection carriers are not indicated. B, Sequencing chromatograms from a patient (top) and a control (bottom). The c.3160C > T mutation is indicated by an arrowhead. C, Relative quantification by pyrosequencing of the mutant versus the wild-type allele in SALL1 cDNA from carrier fibroblasts, before and after treatment by cycloheximide.
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Related In: Results  -  Collection

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fig2: A, Simplified pedigree showing multiple consanguinity loops, CNS-TBS patients represented by filled black circles. For privacy protection carriers are not indicated. B, Sequencing chromatograms from a patient (top) and a control (bottom). The c.3160C > T mutation is indicated by an arrowhead. C, Relative quantification by pyrosequencing of the mutant versus the wild-type allele in SALL1 cDNA from carrier fibroblasts, before and after treatment by cycloheximide.
Mentions: We delineate a novel, autosomal recessive MCA-MR, characterized by TOF, polycystic hypoplastic kidneys with prenatal onset of chronic renal failure, limb and ear malformations, sensorineural deafness, corpus callosum hypoplasia, cortical blindness, and complete lack of psychomotor development (Figure 1), already manifesting prenatally as an abnormal fetal movement pattern. Homozygosity mapping in this consanguineous family (Figure 2, A) revealed a maximal logarithm of the odds score of 1.9 within 5 homozygous intervals located on chromosomes 2, 9, and 16 (data not shown). We selected SALL1 from the largest candidate region for mutation analysis on the basis of partial clinical overlap with TBS, known function and expression patterns. Sequencing identified a homozygous SALL1 mutation, c.3160C > T (p.R1054*), in both affected siblings that segregates with the disease (Figure 2, B). Twelve healthy family members were carriers of this mutation. This novel mutation leads to a premature stop codon in exon 2 and was expected to trigger NMD. Pyrosequencing showed that the mutant transcript was present at 43% of the level of the normal transcript in carrier fibroblasts; this increased to 68% after cycloheximide treatment, indicating a partial contribution of NMD to the relative deficiency of mutant transcript (Figure 2, C). The SALL1 protein encoded by the mutant transcript lacks 270 C-terminal residues including the last double zinc finger domain and a beta-catenin binding domain (Figure 3).1

Bottom Line: Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies.Our findings imply that quantity and quality of SALL1 transcript are important for SALL1 function and determine phenotype, and mode of inheritance, of allelic SALL1-related disorders.This novel MCA-MR emphasizes SALL1 function as critical for normal central nervous system development and warrants a detailed neurologic investigation in all individuals with SALL1 mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Austria. julia.vodopiutz@meduniwien.ac.at

Show MeSH
Related in: MedlinePlus