Circadian abnormalities in mouse models of smith–magenis syndrome: Evidence for involvement of RAI1. Issue 7 (23rd May 2013)

• Record Type: Journal Article
• Authors: Lacaria, Melanie; Gu, Wenli; Lupski, James R
• Is Part Of: American journal of medical genetics. Volume 161:Issue 7(2013:Jul.)
• Page Start: 1561
• Page End: 1568
• Publication Date: 2013-05-23
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.35941
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="ajmga35941-sec-0001" sec-type="section"> <p>Smith–Magenis syndrome (SMS; OMIM 182290) is a genomic disorder characterized by multiple congenital anomalies, intellectual disability, behavioral abnormalities, and disordered sleep resulting from an ∼3.7 Mb deletion copy number variant (CNV) on chromosome 17p11.2 or from point mutations in the gene <italic>RAI1</italic>. The reciprocal duplication of this region results in another genomic disorder, Potocki–Lupski syndrome (PTLS; OMIM 610883), characterized by autism, intellectual disability, and congenital anomalies. We previously used chromosome‐engineering and gene targeting to generate mouse models for PTLS (<italic>Dp(11)17/+</italic>), and SMS due to either deletion CNV or gene knock‐out (<italic>Df(11)17‐2/+</italic> and <italic>Rai1</italic><sup><italic>+/−</italic></sup>, respectively) and we observed phenotypes in these mouse models consistent with their associated human syndromes. To investigate the contribution of individual genes to the circadian phenotypes observed in SMS, we now report the analysis of free‐running period lengths in <italic>Rai1</italic><sup><italic>+/−</italic></sup> and <italic>Df(11)17‐2/+</italic> mice, as well as in mice deficient for another known circadian gene mapping within the commonly deleted/duplicated region, <italic>Dexras1</italic>, and we compare these results to those previously observed in <italic>Dp(11)17/+</italic> mice. Reduced free‐running period lengths were seen in <italic>Df(11)17‐2/+</italic>, <italic>Rai1</italic><sup><italic>+/−</italic></sup>, and <italic>Dexras1</italic><sup><italic>−/−</italic></sup>, but not <italic>Dexras1</italic><sup><italic>+/−</italic></sup> mice, suggesting that <italic>Rai1</italic> may be the primary gene underlying the circadian defects in SMS. However, we cannot rule out the possibility that <italic>cis</italic> effects between multiple haploinsufficient genes in the SMS critical interval (e.g., <italic>RAI1</italic> and <italic>DEXRAS1</italic>) either exacerbate the circadian phenotypes observed in SMS patients with deletions or increase their penetrance in certain environments. This study also confirms a previous report of abnormal circadian function in <italic>Dexras1</italic><sup><italic>−/−</italic></sup> mice. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>