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Mutations in SALL1 and GLI3 are responsible for human limb malformation syndromes. The molecular pathophysiology of these mutations is incompletely understood, and many conclusions have been drawn from studies performed in the mouse. We identified truncating mutations in SALL1 and GLI3 in patients with limb malformation and studied the contribution of nonsense-mediated decay (NMD) to the expression of mutant mRNA in patient-derived fibroblasts. Quantification of the relative proportions of mutant and wild-type alleles was performed by pyrosequencing. In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD. In GLI3, all three mutant alleles tested were susceptible to NMD. This work provides novel insights into the molecular pathophysiology of SALL1 and GLI3 mutations, extends the phenotypic spectrum of SALL1 mutations, and provides an example of a human mutation which does not follow the usual accepted positional rules governing mammalian NMD. (c) 2007 Wiley-Liss, Inc.

Original publication




Journal article


Am j med genet a

Publication Date





3150 - 3160


Alleles, Animals, Cycloheximide, DNA Mutational Analysis, Female, Fibroblasts, Heterozygote, Humans, Kruppel-Like Transcription Factors, Limb Deformities, Congenital, Male, Mice, Models, Genetic, Mutation, Nerve Tissue Proteins, Pedigree, Protein Synthesis Inhibitors, RNA, Messenger, Transcription Factors, Zinc Finger Protein Gli3