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Original article
CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome
  1. F Brioude1,2,
  2. I Oliver-Petit3,
  3. A Blaise2,4,
  4. F Praz2,4,
  5. S Rossignol1,4,
  6. M Le Jule1,
  7. N Thibaud1,
  8. A-M Faussat5,
  9. M Tauber3,6,
  10. Y Le Bouc2,4,
  11. I Netchine1,4
  1. 1AP-HP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France
  2. 2UPMC Univ Paris 06, UMR_S 938, Centre de Recherche Saint Antoine, Paris, France
  3. 3Centre Hospitalo-Universitaire de Toulouse, Hôpital des enfants, Unité d'endocrinologie, génétique, maladies osseuses et gynécologie pédiatrique, Toulouse, France
  4. 4INSERM, UMR_S938, Centre de recherche de Saint-Antoine, Paris, France
  5. 5Université Toulouse III CHU Purpan, UMR 1043 CPTP, Toulouse, France
  6. 6Université Toulouse III CHU Purpan, UMR 1043CPTP, Toulouse, France
  1. Correspondence to Dr Frederic Brioude, Explorations Fonctionnelles Endocriniennes et Biologie Moléculaire, Hôpital Armand Trousseau, 26, avenue du Dr Arnold Netter, Paris 75012, France; frederic.brioude{at}trs.aphp.fr

Abstract

Background Russell Silver syndrome (RSS) leads to prenatal and postnatal growth retardation. About 55% of RSS patients present a loss-of-methylation of the paternal ICR1 domain on chromosome 11p15. CDKN1C is a cell proliferation inhibitor encoded by an imprinted gene in the 11p15 ICR2 domain. CDKN1C mutations lead to Beckwith Wiedemann syndrome (BWS, overgrowth syndrome) and in IMAGe syndrome which associates growth retardation and adrenal insufficiency. We searched for CDKN1C mutations in a cohort of clinically diagnosed RSS patients with no molecular anomaly.

Method The coding sequence and intron–exon boundaries of CDKN1C were analysed in 97 RSS patients. The impact of CDKN1C variants on the cell cycle in vitro were determined by flow cytometry. Stability of CDKN1C was studied by western immunoblotting after inhibition of translation with cycloheximide.

Results We identified the novel c.836G>[G;T] (p.Arg279Leu) mutation in a familial case of intrauterine growth retardation (IUGR) with RSS phenotype and no evidence of IMAGe. All the RSS patients inherited this mutation from their mothers (consistent with monoallelic expression from the maternal allele of the gene). A mutation of this amino acid (p.Arg279Pro) has been reported in cases of IMAGe. Functional analysis showed that Arg279Leu (RSS) did not affect the cell cycle, whereas the Arg279Pro mutation (IMAGe) led to a gain of function. Arg279Leu (RSS) led to an increased stability which could explain an increased activity of CDKN1C.

Conclusions CDKN1C mutations cause dominant maternally transmitted RSS, completing the molecular mirror with BWS. CDKN1C should be investigated in cases with family history of RSS.

  • Clinical genetics
  • Fetal growth
  • Imprinting
  • Russell Silver syndrome
  • CDKN1C

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