The purpose of this research

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression of paternal genes on chromosome 15q11-q12. The PWS locus encompasses multiple genes. The human necdin gene (NDN) is mapped to the PWS locus and not expressed in individuals with PWS. We will focus on the consequences of the loss of expression of the NDN gene for the development of the PWS features in order to understand the mechanisms involved in its pathogenesis and to explore novel therapeutic options.

What is PWS

PWS is a sporadic neurodevelopmental disorder caused by loss of expression of the genes in the PWS region on chromosome 15 with neurologic, cognitive, endocrine and behavioral disturbances. Figure 1 shows genetic map of the PWS region.

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(Fig. 1) Genetic map of the PWS region

The PWS imprinted cluster in human chromosome 15 has its orthologous locus on mouse chromosome 7C. Genetic map of human chromosome 15q11-q13 (upper panel) and syntenic region on mouse chromosome 7B/C (lower panel).

Circles in black show paternal-only expressed genes. The sno RNA cluster encodes intermediate-sized non-coding RNAs (IPW is not snoRNAs).

The imprinted genes involved in PWS on chromosome 15q11-q13 are under the control of an imprinting center (IC).

Genetic map of human chromosome 15q11-q13 (upper panel) and syntenic region on mouse chromosome 7B/C (lower panel). The PWS region on chromosome 15q-q13 that carries the imprinted genes is under the control of an imprinting center (IC). PWS is a neurodevelopmental disorder caused by loss of expression in the PWS region. The exact function of each of these genes in PWS phenotypes is still being elucidated.

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Genetic causes

PWS is a relatively common (prevalence 1/15000-1/30000) sporadic genetic disorder. Molecular classes of PWS and their frequencies are shown in Figure 2.

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Main mechanisms of PWS (Fig. 2)

The parent of origin of each chromosome is indicated with M (maternal) or P (paternal). Maternal uniparental disomy can produce two chromosomes 15 from the mother and none from the father, resulting in no expression from the PWS region.

The parent of origin of each chromosome is indicated with M (maternal) or P (paternal).

Dletion of the paternally contributed 15q11.2-q13 occurs in about 70% of affected individuals. Maternal uniparental disomy 15 (two chromosomes 15 from the mother and none from the father) occurs in about 20-30% of affected individuals.
Maternal uniparental disomy 15 leads to absence of expression of paternally inherited genes in the PWS region.

The imptinting defects account for about 2-5% of cases and demonstrate a maternal-only DNA methylation pattern despite the presence of both the parent alleles.

DNA methylation analysis is the technique that will diagnose PWS correctly in all three molecular classes.
Most widely used DNA methylation tests target the 5′ end of SNURF-SNRPN locus. The promoter region of SNRPN is unmethylated on the paternally expressed allele and methylated on the maternally repressed allele.

Characteristic findings of PWS
Major characteristics
  • Hypotonia with poor suck
    in the naonatal period.
  • Hypothalamic hypogonadism,
    genital hypoplasia and incomplete pubertal development
  • cognitive delays
  • short stature
  • obesity by hyperphagia begins between 1-4 years
  • behavior problems
    (including temper tantrums and compulsive features)
Minor characteristics
  • sleep apnea
  • small hands and feet
  • strabismus
  • seizures
  • osteopenia/osteoporosis
  • decreased saliva volume
  • high pain threshold (decreased recognition of injury)
  • skin picking
Management

Management is symptomatic and supportive.

  • Assuring adequate nutrition in infancy
  • Growth hormone replacement therapy
  • Sex hormones replacement therapy
  • Serotonin agonists in reducing temper outbursts
  • Physical, occupational and speech therapies
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Research project

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We will focus on the consequences of the NDN gene loss of expression on the PWS features to understand the mechanisms involved in its pathogenesis.

A necdin-deficient mouse model shows a number of feature reminiscent of PWS such as a significant decrease in the number of oxytocin-expressing neurons and LHRH neurons in the hypothalamus, high tolerance to thermal pain due to augmented apoptosis in the sensory ganglia, increased skin scraping, and frequent apnea. Thus, necdin may be responsible for at least a subset of the multiple clinical manifestations of PWS.

We will analyze the structual and functional abnormalities during neural development epecially in the hypothalamus using NDN-null mutant mice to understand the pathogenic mechanisms of PWS.

Necdin is a member of the MAGE gene family. While only one MAGE gene (Nse3) exists in the genomes of plants, nematodes, insects and even non-mammalian vertebrates, mammalian cells carry 55 different MAGE genes.

We will analyze the expression and localization of only one MAGE, Nse3 and its binding partner Nse1 and Nse4 derived from the model organisms C. elegance and Dictyostelium in order to understand its basic functions.

We will design chemical compounds that interact with necdin or its related proteins based on 3D structual analysis in silico.

Compounds are screened in laboratory tests for their ability to affect the identified target in in vitro cell culture systems including iPS cells derived from PWS patients. Compounds are also testing in NDN-null mice to assess their efficacy.

Project members

谷浦秀夫

Hideo TaniuraProfessor, College of Pharmaceutical Sciences, Department of Pharmacy

田中秀和

Hidekazu TanakaProfessor, College of Life Sciences, Department of Biomedical Sciences

鈴木 健二

Kenji SuzukiProfessor, College of Pharmaceutical Sciences, Department of Pharmaceutical Siences

正木 聡

So MasakiAsssistant Professor, College of Pharmaceutical Sciences, Department of Pharmacy

添田修平

Shuhei SoedaAsssistant Professor, College of Pharmaceutical Sciences, Department of Pharmacy

中谷仁

Jin NakataniAssociate Professor, College of Life Sciences Department of Biomedical Sciences

澤野俊憲

Toshinori SawanoAssistant Professor, College of Life Sciences, Department of Biomedical Sciences

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