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Cited by 188Genetic Syndromes and ImprintingGenomic variations and chromosomal abnormalitiesWilliams Syndrome Research

Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome

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Bittel, Douglas C., Kibiryeva, Nataliya, Butler, Merlin G.·2006·Pediatrics
DOI 10.1542/peds.2006-0424PMC PMC5453799
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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, messenger-RNA values were positively correlated with assessment parameters, indicating a direct relationship between messenger-RNA levels and better assessment scores, with the highest correlation for NIPA2. The coefficient of determination indicated the quantity of messenger RNA of the 4 genes explained from 24% to 99% of the variation of the behavioral and academic parameters measured. By comparison, the coefficient of determination for deletion type alone explained 5% to 50% of the variation in the assessed parameters. Understanding the influence of gene expression on behavioral and cognitive characteristics in humans is in the early stage of research development. Additional research is needed to identify the function of these genes and their interaction with gene networks to clarify the potential role they play in central nervous system development and function.

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  • Individuals with the larger typical 15q11-q13 type I deletion in Prader-Willi and Angelman syndromes have more severe neurodevelopmental symptoms than those with the smaller typical type II deletion.

    “Several studies have shown that individuals with the larger typical 15q11–q13 type I deletion which is found in both Prader-Willi and Angelman syndromes are reported to have more severe neurodevelopmental symptoms as compared to those individuals with the smaller typical type II deletion [5,6,7,8,9,10].”

    From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [6]

    The Abstract reports that people with Prader-Willi syndrome and the larger type I deletion generally had poorer behavioral and academic outcomes than those with the smaller type II deletion. The cited paper does not report the corresponding symptom comparison for Angelman syndrome, so it supports only the Prader-Willi portion of the claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Copy number variation at the 15q11.2 region is a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia and autism spectrum disorder.

    “Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD).”

    From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [2]

    The Abstract (page not available) links deletions in 15q11–q13 to Prader–Willi syndrome, a neurodevelopmental disorder, and describes behavioral differences between deletion subgroups. It does not identify 15q11.2 copy-number variation as a significant risk locus for schizophrenia or autism spectrum disorder; searches for both conditions found no supporting passage. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The NIPA2 gene accounted for the largest number of significant correlations between mRNA levels and phenotypic features.

    “The NIPA2 gene accounted for the largest number of significant correlations between the mRNA levels and phenotypic features.”

    From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [6]

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Research works printed but not linked: 5

  1. [12]Gunay-Aygun M, Heeger S, Schwartz S, Cassidy SB. Delayed diagnosis in patients with Prader-Willi syndrome due to maternal uniparental disomy 15. Am J Med Genet. 1997;71:106–110. [PubMed] [Google Scholar]
  2. [23]Reiss S. Test Manual for the Reiss Screen for Maladaptive Behavior. Orlando Park, IL: International Diagnostic Systems; 1988. [Google Scholar]
  3. [25]Wechsler D. Wechsler Adult Intelligence Scale-Revised. New York, NY: The Psychological Corporation; 1981. [Google Scholar]
  4. [26]Wechsler D. Wechsler Intelligence Scale for Children-III. New York, NY: The Psychological Corporation; 1991. [Google Scholar]
  5. [28]Woodcock RW, Johnson MB. Woodcock-Johnson Tests of Achievment–Revised. Allen, TX: DLM Teaching Resources; 1990. [Google Scholar]

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Related

Authors
Bittel, D. C., Kibiryeva, N., & Butler, M. G.
Affiliations
Children's Mercy Hospital (US)
ORCID
Venue
Pediatrics
Publisher
American Academy of Pediatrics (AAP)
Published
2006-10-01
Volume
118
Issue
4
Pages
e1276-e1283
ISSN
  • 0031-4005 (ISSN-L)
  • 1098-4275
DOI
10.1542/peds.2006-0424
PMC
PMC5453799
OpenAlex
W2143936008
Cited by
188
References
27
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 10 · 2018: 38 · 2017: 4 · 2016: 7 · 2015: 11 · 2014: 8 · 2013: 4 · 2012: 8
FWCI
4.56
Type
journal article
Language
en
Open access
Locations
  • PEDIATRICS (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD 30329, R01 HD41672, P01HD030329, R01HD041672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
Keywords
Prader-Willi syndrome, chromosome 15q11-q13, NIPA1, CYFIP1, gene expression, mRNA levels, obsessive-compulsive behavior, adaptive behavior, intellectual disability, uniparental disomy 15, imprinting, lymphoblastoid cell lines
MeSH terms
Adolescent, Adult, Chromosomes, Human, Pair 15, Cognition Disorders, Female, Humans, Male, Membrane Proteins, Microtubule-Associated Proteins, Obsessive-Compulsive Disorder, Prader-Willi Syndrome, RNA, Messenger, Gene Expression Profiling, Cation Transport Proteins, Adaptor Proteins, Signal Transducing

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