Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions.
Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions.
Laboratoire de Génétique Moléculaire, CHU Pontchaillou, France ; CNRS UMR 6290, IFR140, Université de Rennes 1, France.
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Dubourg
Psychiatrie, CHRU Bretonneau, Tours, France.
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Bonnet-Brilhault
Génétique, CHRU Bretonneau, Tours, France.
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Toutain
Service de Génétique Clinique, CHU La Pitié Salpêtrière, France ; Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, France.
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Mignot
Service de Génétique Clinique, CHU La Pitié Salpêtrière, France.
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Jacquette
Service de Génétique Clinique, CHU, Lille, France.
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Dieux
Service de Génétique, CHR Clémenceau, Caen, France.
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Gérard
Laboratoire de Génétique Moléculaire, CHU Pontchaillou, France.
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Beaumont-Epinette
Service de Génétique Médicale, CHU Purpan, Toulouse, France.
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Julia
Service de Génétique Médicale, CHU, Nantes, France.
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Isidor
Service de Génétique Clinique, CHU, Lyon-Bron, France.
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Rossi
CNRS UMR 6290, IFR140, Université de Rennes 1, France ; Service de Génétique Médicale, CHU Hôpital Sud, Rennes, Services de, France.
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Odent
CNRS UMR 6290, IFR140, Université de Rennes 1, France.
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Bendavid
Psychiatrie, CHRU Bretonneau, Tours, France.
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Barthélémy
Service de Génétique Clinique, CHU Robert Debré, Paris, France.
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Verloes
Laboratoire de Génétique Moléculaire, CHU Pontchaillou, France ; CNRS UMR 6290, IFR140, Université de Rennes 1, France.
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David
17p11.2; Mutation; RAI1; Smith-Magenis syndrome