Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse

Bi, Weimin; Yan, Jiong; Stankiewicz, P; Park, Sung Sup; Walz, Katherina; Boerkoel, Cornelius F.; Potocki, Lorraine; Shaffer, Lisa G.; Devriendt, Koenraad; Nowaczyk, Magorzata J M; Inoue, Ken; Lupski, James R.

doi:10.1101/gr.73702

Cited by 102 publications

(98 citation statements)

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“…4,5 Human chromosome 17 is syntenic to a approximately 34-cM region of mouse chromosome 11, in which 19 genes are conserved in order and orientation. 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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith-Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17 þ , involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1 41.5-fold and 42-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cagetop hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…The two copies of CMT1A-REP and three SMS-REPs are absent in rodent species (Fig. 6A) (Pentao et al 1992;Chen et al 1997;Probst et al 1999;Bi et al 2002). As an initial segmental duplication event, before the divergence of New World monkeys ∼40-65 Mya, the ∼151-Kb proximal portions of LCR17p, LCR17pA/C, and LCR17pA/D were duplicated and inserted, resulting in the adjacent LCR17pC (Fig.…”

Section: Lcr17pe (mentioning

confidence: 99%

“…Interestingly, Inoue et al (2001) and Bi et al (2002) reported decreased recombination over the ∼1.4-Mb CMT1A and ∼4-Mb SMS genomic regions in proximal 17p, potentially representing the evolutionary remnant of low evolutionary recombination activity. It will be interesting to analyze the recombination activity in other LCR-rich genomic regions.…”

Section: Genome Research 2215mentioning

confidence: 99%

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Serial segmental duplications during primate evolution result in complex human genome architecture

Stankiewicz¹,

Shaw²,

Withers³

et al. 2004

Genome Res.

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The human genome is particularly rich in low-copy repeats (LCRs) or segmental duplications (5%-10%), and this characteristic likely distinguishes us from lower mammals such as rodents. How and why the complex human genome architecture consisting of multiple LCRs has evolved remains an open question. Using molecular and computational analyses of human and primate genomic regions, we analyzed the structure and evolution of LCRs that resulted in complex architectural features of the human genome in proximal 17p. We found that multiple LCRs of different origins are situated adjacent to one another, whereas each LCR changed at different time points between >25 to 3-7 million years ago (Mya) during primate evolution. Evolutionary studies in primates suggested communication between the LCRs by gene conversion. The DNA transposable element MER1-Charlie3 and retroviral ERVL elements were identified at the breakpoint of the t(4;19) chromosome translocation in Gorilla gorilla, suggesting a potential role for transpositions in evolution of the primate genome. Thus, a series of consecutive segmental duplication events during primate evolution resulted in complex genome architecture in proximal 17p. Some of the more recent events led to the formation of novel genes that in human are expressed primarily in the brain. Our observations support the contention that serial segmental duplication events might have orchestrated primate evolution by the generation of novel fusion/fission genes as well as potentially by genomic inversions associated with decreased recombination rates facilitating gene divergence. The genome architecture resulting from the size, orientation, and arrangement of LCRs was shown to be responsible for genomic instability (Lupski 1998;Emanuel and Shaikh 2001;Stankiewicz and Lupski 2002a). Serving as substrates for nonallelic (or "ectopic") homologous recombination (NAHR), LCRs facilitate meiotic and potentially mitotic DNA rearrangements associated with several diseases that are referred to as genomic disorders. Genomic rearrangements can be responsible for Mendelian traits, contiguous gene syndromes, and whole-arm chromosome aberrations (Lupski 1998Stankiewicz and Lupski 2002a). During the last decade, substantial molecular data have emerged documenting that LCR-mediated NAHR is a major mechanism for human disease (Emanuel and Shaikh 2001;Stankiewicz and Lupski 2002a;Shaw and Lupski 2004).Several studies have shown that LCRs arose recently, apparently during primate evolution (Stankiewicz and Lupski 2002b). Recent data suggest that LCR-associated genome architecture does not represent simple segmental duplications but rather reflects complex rearrangements that are potentially the end product of multiple events (van Geel et al. 2002). These serial segmental duplications can result in a complex shuffling of genomic sequences (Babcock et al. 2003;.The gene-and LCR-rich human genomic region 17p11.2-p12 is rearranged in a variety of different constitutional, evolutionary, and cancer-associated structural chromoso...

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“…Next we undertook systematic sequencing of genes in individual SMS129 beginning with three genes localized to the SMS critical interval 4,6,8 : developmentally regulated GTP binding protein 2 (DRG2), RAS dexamethasone-induced 1 (RASD1) and retinoic acid induced 1 (RAI1). We identified no mutations in either RASD1 or DRG2 but found a deletion of 29 bp in exon 3 of RAI1 on one allele in individual SMS129 (Fig.…”

mentioning

confidence: 99%