Homozygous SALL1 Mutation Causes a Novel Multiple Congenital Anomaly—Mental Retardation Syndrome - 26/02/13
, Heinz Zoller, MD, PhD 2, Aimée L. Fenwick, MPhil 3, Richard Arnhold, MD 4, Max Schmid, MD 5, Daniela Prayer, MD 6, Thomas Müller, MD 7, Andreas Repa, MD 1, Arnold Pollak, MD 1, Christoph Aufricht, MD 1, Andrew O.M. Wilkie, DM, FRCP 3, Andreas R. Janecke, MD 7, 8
Reprint requests: Julia Vodopiutz, MD, Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Währingergürtel 18-20, A-1090 Vienna, Austria.Abstract |
Objective |
To delineate a novel autosomal recessive multiple congenital anomaly-mental retardation (MCA-MR) syndrome in 2 female siblings of a consanguineous pedigree and to identify the disease-causing mutation.
Study design |
Both siblings were clinically characterized and homozygosity mapping and sequencing of candidate genes were applied. The contribution of nonsense-mediated messenger RNA (mRNA) decay to the expression of mutant mRNA in fibroblasts of a healthy carrier and a control was studied by pyrosequencing.
Results |
We identified the first homozygous SALL1 mutation, c.3160C > T (p.R1054*), in 2 female siblings presenting with multiple congenital anomalies, central nervous system defects, cortical blindness, and absence of psychomotor development (ie, a novel recognizable, autosomal recessive MCA-MR). The mutant SALL1 transcript partially undergoes nonsense-mediated mRNA decay and is present at 43% of the normal transcript level in the fibroblasts of a healthy carrier.
Conclusion |
Previously heterozygous SALL1 mutations and deletions have been associated with dominantly inherited anal-renal-radial-ear developmental anomalies. We identified an allelic recessive SALL1-related MCA-MR. 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.
Le texte complet de cet article est disponible en PDF.Keyword : cDNA, CNS, CNS-TBS, mRNA, MCA-MR, NMD, TBS, TOF
Plan
| Funded partially by the Wellcome Trust (to A.W.). The authors declare no conflicts of interest. |
Vol 162 - N° 3
P. 612-617 - mars 2013 Retour au numéro
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