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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, Schematic of SALL1 protein, localization of known mutations and the best characterized SALL1 interaction domains: SALL1 (1324 aa) harbors 10 zinc finger domains (black boxes) and heterochromatin (*), beta-catenin (#), and SALL1,2,3,4 (+) binding sites. In TBS all previously reported mutations are heterozygous truncating mutations (arrows). The majority of mutations cluster in a hot spot region and result in 5′-truncation, but late 3′-truncating mutations and heterozygous whole gene deletions are also described in mild TBS. CNS-TBS is caused by a novel homozygous late 3′-truncating mutation p.R1054*. B, Amount of wild-type (white) and truncated (gray) SALL1 protein in relation to phenotypic expression in humans. In the presented model the remaining transcript is assumed to represent the level of protein. Healthy subjects express 50% of the wild-type SALL1 protein per allele. CNS-TBS patients express 21% 3′-truncated SALL1 protein per mutant allele and no wild-type protein due to homozygous p.R1054* mutation which partially undergoes NMD. CNS-TBS carriers are healthy and express 50% wild-type SALL1 protein and 21% 3′-truncated SALL1 protein. All TBS patients express 50% wild-type SALL1 protein from the wild-type allele. Classical TBS patients express additionally 50% 5′-truncated SALL1 protein due to 5′-hot spot mutations which escape NMD. There are 3 patients with mild TBS due to haploinsufficiency caused by heterozygous gene deletion. Patients with mild TBS due to p.C1139Wfs*14 mutation, which partially undergo NMD express additional 22% late-truncated SALL1 protein. C, SALL1 mouse models corresponding to B, Heterozygous Sall1ΔZn2-10 mice, expressing truncated SALL1 protein, present with a dominant TBS phenotype including limb defects and hearing loss,14 whereas Sall1−/− mice present with autosomal recessive isolated bilateral renal agenesis and no phenotype in heterozygotes.13 The phenotype in both CNS-TBS patients does not correspond to the phenotype in homozygous Sall1−/− mice but resembles the more severe phenotype seen in homozygous Sall1ΔZn2-10 mice including renal agenesis (100%), limb defects (57%), anal malformations (>50%), and neural tube closure defects (38%). WT, wild-type.
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fig3: A, Schematic of SALL1 protein, localization of known mutations and the best characterized SALL1 interaction domains: SALL1 (1324 aa) harbors 10 zinc finger domains (black boxes) and heterochromatin (*), beta-catenin (#), and SALL1,2,3,4 (+) binding sites. In TBS all previously reported mutations are heterozygous truncating mutations (arrows). The majority of mutations cluster in a hot spot region and result in 5′-truncation, but late 3′-truncating mutations and heterozygous whole gene deletions are also described in mild TBS. CNS-TBS is caused by a novel homozygous late 3′-truncating mutation p.R1054*. B, Amount of wild-type (white) and truncated (gray) SALL1 protein in relation to phenotypic expression in humans. In the presented model the remaining transcript is assumed to represent the level of protein. Healthy subjects express 50% of the wild-type SALL1 protein per allele. CNS-TBS patients express 21% 3′-truncated SALL1 protein per mutant allele and no wild-type protein due to homozygous p.R1054* mutation which partially undergoes NMD. CNS-TBS carriers are healthy and express 50% wild-type SALL1 protein and 21% 3′-truncated SALL1 protein. All TBS patients express 50% wild-type SALL1 protein from the wild-type allele. Classical TBS patients express additionally 50% 5′-truncated SALL1 protein due to 5′-hot spot mutations which escape NMD. There are 3 patients with mild TBS due to haploinsufficiency caused by heterozygous gene deletion. Patients with mild TBS due to p.C1139Wfs*14 mutation, which partially undergo NMD express additional 22% late-truncated SALL1 protein. C, SALL1 mouse models corresponding to B, Heterozygous Sall1ΔZn2-10 mice, expressing truncated SALL1 protein, present with a dominant TBS phenotype including limb defects and hearing loss,14 whereas Sall1−/− mice present with autosomal recessive isolated bilateral renal agenesis and no phenotype in heterozygotes.13 The phenotype in both CNS-TBS patients does not correspond to the phenotype in homozygous Sall1−/− mice but resembles the more severe phenotype seen in homozygous Sall1ΔZn2-10 mice including renal agenesis (100%), limb defects (57%), anal malformations (>50%), and neural tube closure defects (38%). WT, wild-type.

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, Schematic of SALL1 protein, localization of known mutations and the best characterized SALL1 interaction domains: SALL1 (1324 aa) harbors 10 zinc finger domains (black boxes) and heterochromatin (*), beta-catenin (#), and SALL1,2,3,4 (+) binding sites. In TBS all previously reported mutations are heterozygous truncating mutations (arrows). The majority of mutations cluster in a hot spot region and result in 5′-truncation, but late 3′-truncating mutations and heterozygous whole gene deletions are also described in mild TBS. CNS-TBS is caused by a novel homozygous late 3′-truncating mutation p.R1054*. B, Amount of wild-type (white) and truncated (gray) SALL1 protein in relation to phenotypic expression in humans. In the presented model the remaining transcript is assumed to represent the level of protein. Healthy subjects express 50% of the wild-type SALL1 protein per allele. CNS-TBS patients express 21% 3′-truncated SALL1 protein per mutant allele and no wild-type protein due to homozygous p.R1054* mutation which partially undergoes NMD. CNS-TBS carriers are healthy and express 50% wild-type SALL1 protein and 21% 3′-truncated SALL1 protein. All TBS patients express 50% wild-type SALL1 protein from the wild-type allele. Classical TBS patients express additionally 50% 5′-truncated SALL1 protein due to 5′-hot spot mutations which escape NMD. There are 3 patients with mild TBS due to haploinsufficiency caused by heterozygous gene deletion. Patients with mild TBS due to p.C1139Wfs*14 mutation, which partially undergo NMD express additional 22% late-truncated SALL1 protein. C, SALL1 mouse models corresponding to B, Heterozygous Sall1ΔZn2-10 mice, expressing truncated SALL1 protein, present with a dominant TBS phenotype including limb defects and hearing loss,14 whereas Sall1−/− mice present with autosomal recessive isolated bilateral renal agenesis and no phenotype in heterozygotes.13 The phenotype in both CNS-TBS patients does not correspond to the phenotype in homozygous Sall1−/− mice but resembles the more severe phenotype seen in homozygous Sall1ΔZn2-10 mice including renal agenesis (100%), limb defects (57%), anal malformations (>50%), and neural tube closure defects (38%). WT, wild-type.
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fig3: A, Schematic of SALL1 protein, localization of known mutations and the best characterized SALL1 interaction domains: SALL1 (1324 aa) harbors 10 zinc finger domains (black boxes) and heterochromatin (*), beta-catenin (#), and SALL1,2,3,4 (+) binding sites. In TBS all previously reported mutations are heterozygous truncating mutations (arrows). The majority of mutations cluster in a hot spot region and result in 5′-truncation, but late 3′-truncating mutations and heterozygous whole gene deletions are also described in mild TBS. CNS-TBS is caused by a novel homozygous late 3′-truncating mutation p.R1054*. B, Amount of wild-type (white) and truncated (gray) SALL1 protein in relation to phenotypic expression in humans. In the presented model the remaining transcript is assumed to represent the level of protein. Healthy subjects express 50% of the wild-type SALL1 protein per allele. CNS-TBS patients express 21% 3′-truncated SALL1 protein per mutant allele and no wild-type protein due to homozygous p.R1054* mutation which partially undergoes NMD. CNS-TBS carriers are healthy and express 50% wild-type SALL1 protein and 21% 3′-truncated SALL1 protein. All TBS patients express 50% wild-type SALL1 protein from the wild-type allele. Classical TBS patients express additionally 50% 5′-truncated SALL1 protein due to 5′-hot spot mutations which escape NMD. There are 3 patients with mild TBS due to haploinsufficiency caused by heterozygous gene deletion. Patients with mild TBS due to p.C1139Wfs*14 mutation, which partially undergo NMD express additional 22% late-truncated SALL1 protein. C, SALL1 mouse models corresponding to B, Heterozygous Sall1ΔZn2-10 mice, expressing truncated SALL1 protein, present with a dominant TBS phenotype including limb defects and hearing loss,14 whereas Sall1−/− mice present with autosomal recessive isolated bilateral renal agenesis and no phenotype in heterozygotes.13 The phenotype in both CNS-TBS patients does not correspond to the phenotype in homozygous Sall1−/− mice but resembles the more severe phenotype seen in homozygous Sall1ΔZn2-10 mice including renal agenesis (100%), limb defects (57%), anal malformations (>50%), and neural tube closure defects (38%). WT, wild-type.
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