Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith–Magenis syndrome

Abstract

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with del(17)(p11.2p11.2). The phenotype is variable even in patients with deletions of the same size. RAI1 has been recently suggested as a major gene for majority of the SMS phenotypes, but its role in the full spectrum of the phenotype remains unclear. Df(11)17/+ mice contain a heterozygous deletion in the mouse region syntenic to the SMS common deletion, and exhibit craniofacial abnormalities, seizures and marked obesity, partially reproducing the SMS phenotype. To further study the genetic basis for the phenotype, we constructed three lines of mice with smaller deletions [Df(11)17-1, Df(11)17-2 and Df(11)17-3] using retrovirus-mediated chromosome engineering to create nested deletions. Both craniofacial abnormalities and obesity have been observed, but the penetrance of the craniofacial phenotype was markedly reduced when compared with Df(11)17/+ mice. Overt seizures were not observed. Phenotypic variation has been observed in mice with the same deletion size in the same and in different genetic backgrounds, which may reflect the variation documented in the patients. These results indicate that the smaller deletions contain the gene(s), most likely Rai1, causing craniofacial abnormalities and obesity. However, genes or regulatory elements in the larger deletion, which are not located in the smaller deletions, as well as genes located elsewhere, also influence penetrance and expressivity of the phenotype. Our mouse models refined the genomic region important for a portion of the SMS phenotype and provided a basis for further molecular analysis of genes associated with SMS.

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

“…28,29 Mouse models for SMS and dup(17)(p11.2p11.2) syndromes, Df(11)17 þ and Dp(11)17 þ , heterozygous for either a deletion or a duplication, respectively, encompassing an approximately 3 Mb mouse syntenic region, have been created, while a gene targeting approach was used to create Rai1 þ /À mice (Table 3). 30,31 Studies showed that both the deletion 31,34 and the Rai1 þ /À mice 30 manifested with craniofacial abnormalities, obesity, altered circadian rhythm, seizures, and hypoactivity, with the few viable Rai1 À/À mice exhibiting severe neurological abnormalities, motor dysfunction, overt seizures, and learning deficits (Table 3). 33 Evaluation of the duplication mice showed hyperactivity, reduced weight, and impaired fear conditioning.…”

Evolution and diversity of copy number variation in the great ape lineage

“…Edelman et al (2007) found that individuals with RAI1 mutations and deletions were likely to be obese. Mouse models of RAI1 deletions additionally demonstrated an obese phenotype for deletions but not duplications of the critical locus (Walz et al 2003;Yan et al 2004); duplications conferred an underweight phenotype. A null RAI1 allele in mice generated by Bi et al (2005) also exhibited obesity.…”

Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf–Hirschhorn syndrome

“…Firstly, mutations in modifier genes located outside the deleted region may either enhance or suppress the severity of the disorder, as has been suggested in a mouse model of deletions in 17p11.2 associated with SmithMagenis syndrome. 5 Secondly, observations on monozygotic twins with identical 22q11.2 microdeletions but discordant clinical phenotypes 6 suggest that post-zygotic mutational events, environmental influences, or stochastic factors affecting gene expression may cause phenotypic variation. Thirdly, position effects may affect clinical manifestations of chromosomal alterations, such that genes closely located to telomeres, for example in the WHSCR, may be particularly sensitive to gene silencing.…”