Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Abstract

Prader-Willi syndrome is a neurodevelopmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia (leading to obesity in early childhood), learning problems, and behavioral difficulties. A paternal 15q11-q13 deletion is found in ~70% of patients with Prader-Willi syndrome, ~25% have uniparental maternal disomy 15, and the remaining 2% to 5% have imprinting defects. The proximal deletion breakpoint in the 15q11-q13 region occurs at 1 of 2 sites located within either of 2 large duplicons allowing for the identification of 2 deletion subgroups. The larger, type I (TI) deletion involves breakpoint 1, which is close to the centromere, whereas the smaller, type II (TII) deletion involves breakpoint 2, located ~500 kilobases distal to breakpoint 1. Breakpoint 3 is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Analyses of the genetic subtypes of Prader-Willi syndrome to date have primarily compared individuals with typical deletion and uniparental maternal disomy 15 without grouping the individuals with a deletion into TI or TII. Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters. We previously presented the first assessment of clinical differences in individuals with Prader-Willi syndrome categorized as having type I or II deletions. Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15. Four genes (NIPA1, NIPA2, CYFIP1, and GCP5) have been identified in the chromosomal region between breakpoints 1 and 2 and are implicated in compulsive behavior and lower intellectual ability observed in individuals with Prader-Willi syndrome with TI versus TII deletions. We quantified messenger-RNA levels of these 4 genes in actively growing lymphoblastoid cells derived from 8 subjects with Prader-Willi syndrome with the TI deletion (4 males, 4 females; mean: age 25.2 ± 8.9 years) and 9 with the TII deletion (3 males, 6 females; mean age: 19.5 ± 5.8 years). Messenger-RNA levels were correlated with validated psychological and behavioral scales administered by trained psychologists blinded to genotype status. Messenger RNA from NIPA1, NIPA2, CYFIP1, and GCP5 was reduced but detectable in the subjects with Prader-Willi syndrome with the TI deletion, supporting biallelic expression. For the most part, Address correspondence to Merlin G. Butler, MD, PhD, Children's Mercy Hospitals and Clinics, Section of Medical Genetics and Molecular Medicine, 2401 Gillham Rd, Kansas City, MO 64108. mgbutler@cmh.edu. The authors have indicated they have no financial relationships relevant to this article to disclose. Prader-willi syndrom...

Array comparative genomic hybridization (aCGH) analysis in Prader–Willi syndrome

“…We previously reported the first association of larger deletion size in PWS and poorer clinical outcomes [Butler et al, 2004] and described an association between expression levels of the four reported genes between BP1 and BP2 and aberrant behavior [Bittel et al, 2006]. Our aCGH analysis also shows larger deletions than previously identified with more variation in size.…”

“…Several copy number variants outside the Prader-Willi chromosome region (e.g., 3q, 8p) were confirmed using quantitative PCR with primers specific to the region of interest (i.e., deleted or duplicated) and compared to CNVs reported in the human genome (see http://projects.tcag.ca/variation/). Equal quantities of genomic DNA from PWS subjects and chromosomally normal comparison subjects were added to a hot-start quantitative PCR mix including SYBR green (Invitrogen, Inc., Carlsbad, CA) and PCR performed in an ABI 7000 thermocycler according to the manufacturer's instructions as previously described [Bittel et al, 2006[Bittel et al, , 2007b. Five replicates of each sample were run.…”

Advances in autism genetics: on the threshold of a new neurobiology

“…The use of gene expression data will increase as sample sizes grow, as additional molecularly defined syndromes are characterized by expression arrays 37,44 and as expression information is better integrated with comprehensive phenotypic data 81 . It is also likely that the integration of expression studies with high-density SNP arrays will ultimately come to elucidate how disease-associated variants affect cellular function 82 .…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Cyfip1 and Cyfip2 are members of a highly conserved gene family 52 , and dysregulation of Cyfip1 expression levels leads to pathological changes in neuronal maturation and connectivity, both of which may contribute to the development of the neurological symptoms observed in ASD and schizophrenia 63 . A CNV in the 15q11.2 region of the human genome has been implicated in several neurological and neuropsychiatric conditions [64][65][66][67][68][69][70] and a CYFIP1 CNV within 15q11.2 has been linked to ASD 71 , with an upregulation of CYFIP1 mRNA being demonstrated in genomewide expression profiling of ASD patients with 15q11-q13 duplication 72 . A rare CYFIP1 deletion has also been reported in a patient with a mild intellectual disability and a pervasive developmental disorder not otherwise specified 71 .…”