Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Diana Braunholz, Melanie Hullings, María Concepcion Gil-Rodríguez, Christopher T. Fincher, Mark B. Mallozzi, Elizabeth Loy, Melanie Albrecht, Maninder Kaur, Janusz Limon, Abhinav Rampuria, Dinah Clark, Antonie Debra Kline, Juliane Eckhold, Andreas Tzschach, Raoul Hennekam, Gabriele Gillessen-Kaesbach, Jolanta Wierzba, Ian D. Krantz, Matthew A. Deardorff, Frank J. Kaiser

Research output: Contribution to journalArticle

Abstract

Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIBPL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIBPL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

Original languageEnglish (US)
Pages (from-to)271-276
Number of pages6
JournalEuropean Journal of Human Genetics
Volume20
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

De Lange Syndrome
Missense Mutation
Chromatids
Mutation
Siblings
Yeasts
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Amphibians
Chromatin
Vertebrates
Extremities
Growth
Proteins

Keywords

  • cohesin
  • Cornelia de Lange syndrome
  • MAU2
  • NIPBL
  • SCC4
  • sister chromatid cohesion

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Braunholz, D., Hullings, M., Gil-Rodríguez, M. C., Fincher, C. T., Mallozzi, M. B., Loy, E., ... Kaiser, F. J. (2012). Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction. European Journal of Human Genetics, 20(3), 271-276. https://doi.org/10.1038/ejhg.2011.175

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction. / Braunholz, Diana; Hullings, Melanie; Gil-Rodríguez, María Concepcion; Fincher, Christopher T.; Mallozzi, Mark B.; Loy, Elizabeth; Albrecht, Melanie; Kaur, Maninder; Limon, Janusz; Rampuria, Abhinav; Clark, Dinah; Kline, Antonie Debra; Eckhold, Juliane; Tzschach, Andreas; Hennekam, Raoul; Gillessen-Kaesbach, Gabriele; Wierzba, Jolanta; Krantz, Ian D.; Deardorff, Matthew A.; Kaiser, Frank J.

In: European Journal of Human Genetics, Vol. 20, No. 3, 03.2012, p. 271-276.

Research output: Contribution to journalArticle

Braunholz, D, Hullings, M, Gil-Rodríguez, MC, Fincher, CT, Mallozzi, MB, Loy, E, Albrecht, M, Kaur, M, Limon, J, Rampuria, A, Clark, D, Kline, AD, Eckhold, J, Tzschach, A, Hennekam, R, Gillessen-Kaesbach, G, Wierzba, J, Krantz, ID, Deardorff, MA & Kaiser, FJ 2012, 'Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction', European Journal of Human Genetics, vol. 20, no. 3, pp. 271-276. https://doi.org/10.1038/ejhg.2011.175
Braunholz D, Hullings M, Gil-Rodríguez MC, Fincher CT, Mallozzi MB, Loy E et al. Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction. European Journal of Human Genetics. 2012 Mar;20(3):271-276. https://doi.org/10.1038/ejhg.2011.175
Braunholz, Diana ; Hullings, Melanie ; Gil-Rodríguez, María Concepcion ; Fincher, Christopher T. ; Mallozzi, Mark B. ; Loy, Elizabeth ; Albrecht, Melanie ; Kaur, Maninder ; Limon, Janusz ; Rampuria, Abhinav ; Clark, Dinah ; Kline, Antonie Debra ; Eckhold, Juliane ; Tzschach, Andreas ; Hennekam, Raoul ; Gillessen-Kaesbach, Gabriele ; Wierzba, Jolanta ; Krantz, Ian D. ; Deardorff, Matthew A. ; Kaiser, Frank J. / Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction. In: European Journal of Human Genetics. 2012 ; Vol. 20, No. 3. pp. 271-276.
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abstract = "Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60{\%} of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIBPL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIBPL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.",
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AU - Fincher, Christopher T.

AU - Mallozzi, Mark B.

AU - Loy, Elizabeth

AU - Albrecht, Melanie

AU - Kaur, Maninder

AU - Limon, Janusz

AU - Rampuria, Abhinav

AU - Clark, Dinah

AU - Kline, Antonie Debra

AU - Eckhold, Juliane

AU - Tzschach, Andreas

AU - Hennekam, Raoul

AU - Gillessen-Kaesbach, Gabriele

AU - Wierzba, Jolanta

AU - Krantz, Ian D.

AU - Deardorff, Matthew A.

AU - Kaiser, Frank J.

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N2 - Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIBPL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIBPL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

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