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Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki-Lupski syndrome diagnosis.

ABSTRACT: The identification of structural variants of uncertain clinical significance is increasing; however, studies delineating the functional consequence of these variants in the pathogenicity of phenotypic features are lacking. Understanding the consequence of structural variants such as copy number alterations and their role in gene expression changes is paramount in order to perform a comprehensive analysis of genetic effects on phenotypic variation and disease. RAI1 is a dosage-sensitive essential neurodevelopmental gene. Copy number loss of RAI1 results in Smith-Magenis syndrome while copy number gain results in Potocki-Lupski syndrome. Here, we present a case of a six year old female with a newly identified maternally inherited copy number loss that lies within the Smith-Magenis syndrome common deletion region, but RAI1 copy number is normal. Integration of the Encyclopedia of DNA Elements (ENCODE) data at the affected region suggests that the deletion disrupts several cis-acting regulatory elements upstream of RAI1, such as multiple repressor sites and an insulator region. Gene expression studies revealed that both the proband and the mother have significantly elevated RAI1 mRNA levels suggesting that the structural variant alters gene expression regulation. The proband and the mother both have some features of Potocki-Lupski syndrome, while the child appears to be more affected with autistic-like features. Overall, our work demonstrates that the integration of ENCODE data with structural variants of uncertain significance aids in delineating a functional consequence to a genomic aberration and subsequent diagnosis.

SUBMITTER: Alaimo JT

PROVIDER: S-EPMC4594966 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki-Lupski syndrome diagnosis.

Alaimo Joseph T JT Mullegama Sureni V SV Thomas Mary Ann MA Elsea Sarah H SH

Molecular cytogenetics 20151005

The identification of structural variants of uncertain clinical significance is increasing; however, studies delineating the functional consequence of these variants in the pathogenicity of phenotypic features are lacking. Understanding the consequence of structural variants such as copy number alterations and their role in gene expression changes is paramount in order to perform a comprehensive analysis of genetic effects on phenotypic variation and disease. RAI1 is a dosage-sensitive essential ...[more]

PMID: 26442755

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Project description:Retinoic acid induced 1 ( RAI1 ) encodes a dosage-sensitive gene that when haploinsufficient results in Smith-Magenis syndrome (SMS) and when overexpressed results in Potocki-Lupski syndrome (PTLS). Phenotypic and molecular evidence illustrates that haploinsufficiency of RAI1 disrupts circadian rhythm through the dysregulation of the master circadian regulator, circadian locomotor output cycles kaput ( CLOCK) , and other core circadian components, contributing to prominent sleep disturbances in SMS. However, the phenotypic and molecular characterization of sleep features in PTLS has not been elucidated. Using the Pittsburgh Sleep Quality Index (PSQI), caregivers of 15 school-aged children with PTLS reported difficulties in initiating sleep. Indeed, more than 70% of individuals manifested moderate to severe sleep latency, as defined by the PSQI. Moreover, these individuals manifested difficulties in sleep maintenance, with middle of the night and early morning awakenings. When assessing daytime sleepiness through the Epworth Sleepiness Scale, approximately 21% of the individuals manifested excessive daytime somnolence. This indicates that mild dyssomnia characterizes the majority of the sleep phenotype, with occasionally problematic daytime somnolence, a phenotype different than that expressed by individuals with SMS, where daytime sleepiness is a chronic problem. Gene expression analysis of the core circadian machinery in the hypothalamus of the PTLS mouse model ( Rai1 -Tg) found significant dysregulation of the transcriptional activators, Clock and Arntl , and the transcriptional repressors, Per1-3 and Cry1/2 , during both light and dark phases. These findings suggest a partial loss of circadian entrainment typically evoked by environmental photic cues. Examination of circadian clock gene expression in the Rai1- Tg mouse heart, liver, and kidney found unchanged expression of Clock and most of its downstream targets during both light and dark phases, suggesting an asynchronized circadian rhythm. Furthermore, examination of circadian gene expression in synchronized PTLS lymphoblasts revealed reduced transcripts of the Period ( PER1-3 ) family and normal expression of CRY1/2 . The finding that central circadian gene expression was altered while many peripheral circadian components were intact suggests a tissue-specific circadian uncoupling of the circadian machinery due to Rai1 overexpression. Overall, our results demonstrate that overexpression of RAI1 results in sleep deficiencies in individuals with PTLS due to a lack of properly regulated circadian machinery gene expression and highlight the importance of evaluating sleep concerns in individuals with PTLS.

Dataset Information

Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki-Lupski syndrome diagnosis.

Publications

Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki-Lupski syndrome diagnosis.

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