Deficiency of the cyclin-dependent kinase inhibitor, CDKN1B, results in overgrowth and neurodevelopmental delay

William Grey, Louise Izatt, Wafa Sahraoui, Yiu-Ming Ng, Caroline Ogilvie, Anthony Hulse, Eric Tse, Roman Holic, Veronica Yu

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay.

Original languageEnglish
Pages (from-to)864-8
Number of pages5
JournalHuman Mutation
Volume34
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Autistic Disorder/genetics
  • Child, Preschool
  • Comparative Genomic Hybridization
  • Cyclin-Dependent Kinase Inhibitor p27/deficiency
  • Developmental Disabilities/diagnosis
  • Female
  • Gene Expression
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Polymorphism, Single Nucleotide

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