Identification of Uncommon Recurrent Potocki-Lupski Syndrome-Associated Duplications and the Distribution of Rearrangement Types and Mechanisms in PTLS

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2010; 86(3):462-70. DOI: 10.1016/j.ajhg.2010.02.001
Source: PubMed


Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.

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    • "These models suggest that during replication downstream fork switching results in a deletion, whereas switching to an upstream fork results in duplication and repeated switches back and forth result in complex rearrangements such as triplications and inversions. Previous studies involving replication-based models have been used to explain the mechanism of gross rearrangements in genes causing genomic disorders such as Pelizaeus-Merzbacher disease (Lee et al. 2007), Rett syndrome (Carvalho et al. 2009), and CMT1A/HNPP (Zhang et al. 2010). Complex genomic rearrangements (CGR) in DMD are rare but have been demonstrated (White et al. 2006; Zhang et al. 2008; Oshima et al. 2009; Ishmukhametova et al. 2013, 2012). "
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    ABSTRACT: Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2–5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45–49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.
    11/2014; 2(6). DOI:10.1002/mgg3.108
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    • "Most SMS deletions and reciprocal duplications have common breakpoints, although deletions and duplications of different sizes have been identified. Both appear to involve a common 1.3-3.7 Mb chromosome section in 17p11.2 that includes the RAI1 gene (5, 8, 9). Previous studies (10-13) have provided evidence that the number of RAI1 copies is most likely responsible for these syndromes. "
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    ABSTRACT: Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is a well-known developmental disorder. Potocki-Lupski syndrome has recently been recognized as a microduplication syndrome that is a reciprocal disease of Smith-Magenis syndrome. In this paper, we report on the clinical and cytogenetic features of two Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome. Patient 1 (Smith-Magenis syndrome) was a 2.9-yr-old boy who showed mild dysmorphic features, aggressive behavioral problems, and developmental delay. Patient 2 (Potocki-Lupski syndrome), a 17-yr-old boy, had only intellectual disabilities and language developmental delay. We used array comparative genomic hybridization (array CGH) and found a 2.6 Mb-sized deletion and a reciprocal 2.1 Mb-sized duplication involving the 17p11.2. These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF.
    Journal of Korean medical science 12/2012; 27(12):1586-90. DOI:10.3346/jkms.2012.27.12.1586 · 1.27 Impact Factor
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    • "with clinical features including infantile hypotonia, structural cardiovascular anomalies, intellectual disability and features of autistic spectrum disorder [16]. Findings with mouse models for PTLS [17] and the identification of PTLS patients with nonrecurrent duplications containing only RAI1 in the rearranged interval [18], represent strong evidence to show RAI1 as the predominant gene responsible for the PTLS phenotype. RAI1 has also been linked with response to neuroleptics in schizophrenia and with the age of onset of spinocerebellar ataxia type 2 [19], [20]. "
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    ABSTRACT: Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation.
    PLoS ONE 09/2012; 7(9):e45155. DOI:10.1371/journal.pone.0045155 · 3.23 Impact Factor
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