Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein

Andrew Dauber, Stephen Lafranchi, Zoltan Maliga, Julian C. Lui, Jennifer E. Moon, Cailin McDeed, Katrin Henke, Jonathan (Jon) Zonana, Garrett A. Kingman, Tune H. Pers, Jeffrey Baron, Ronald (Ron) Rosenfeld, Joel N. Hirschhorn, Matthew P. Harris, Vivian Hwa

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Context: Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions. Objective: The objective of the study was to find the genetic etiology of a novel presentation of MPD. Design: The design of the study was whole-exome sequencing performed on two affected sisters in a single family. Molecular and functional studies of a candidate gene were performed using patient-derived primary fibroblasts and a zebrafish morpholino oligonucleotides knockdown model. Patients: Two sisters presented with a novel subtype of MPD, including severe intellectual disabilities. Main Outcome Measures: NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied. Results: From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes. In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype. Conclusion: We identified a novel clinical subtype of MPD in two sisters who have rare variants in NIN. We show, for the first time, that reduction of ninein function in the developing zebrafish leads to specific deficiencies of brain and skull development, offering a developmental basis for the myriad phenotypes in our patients.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Dwarfism
Zebrafish
Genes
Skull
Fibroblasts
Siblings
Proteins
Morpholinos
Defects
Asymmetric Cell Division
Exome
Neural Plate
Phenotype
Centrosome
Inborn Genetic Diseases
Brain
Heterozygote
Growth
Morphogenesis
Intellectual Disability

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. / Dauber, Andrew; Lafranchi, Stephen; Maliga, Zoltan; Lui, Julian C.; Moon, Jennifer E.; McDeed, Cailin; Henke, Katrin; Zonana, Jonathan (Jon); Kingman, Garrett A.; Pers, Tune H.; Baron, Jeffrey; Rosenfeld, Ronald (Ron); Hirschhorn, Joel N.; Harris, Matthew P.; Hwa, Vivian.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 11, 11.2012.

Research output: Contribution to journalArticle

Dauber, A, Lafranchi, S, Maliga, Z, Lui, JC, Moon, JE, McDeed, C, Henke, K, Zonana, JJ, Kingman, GA, Pers, TH, Baron, J, Rosenfeld, RR, Hirschhorn, JN, Harris, MP & Hwa, V 2012, 'Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 11. https://doi.org/10.1210/jc.2012-2150
Dauber, Andrew ; Lafranchi, Stephen ; Maliga, Zoltan ; Lui, Julian C. ; Moon, Jennifer E. ; McDeed, Cailin ; Henke, Katrin ; Zonana, Jonathan (Jon) ; Kingman, Garrett A. ; Pers, Tune H. ; Baron, Jeffrey ; Rosenfeld, Ronald (Ron) ; Hirschhorn, Joel N. ; Harris, Matthew P. ; Hwa, Vivian. / Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 11.
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abstract = "Context: Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions. Objective: The objective of the study was to find the genetic etiology of a novel presentation of MPD. Design: The design of the study was whole-exome sequencing performed on two affected sisters in a single family. Molecular and functional studies of a candidate gene were performed using patient-derived primary fibroblasts and a zebrafish morpholino oligonucleotides knockdown model. Patients: Two sisters presented with a novel subtype of MPD, including severe intellectual disabilities. Main Outcome Measures: NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied. Results: From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes. In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype. Conclusion: We identified a novel clinical subtype of MPD in two sisters who have rare variants in NIN. We show, for the first time, that reduction of ninein function in the developing zebrafish leads to specific deficiencies of brain and skull development, offering a developmental basis for the myriad phenotypes in our patients.",
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AU - Moon, Jennifer E.

AU - McDeed, Cailin

AU - Henke, Katrin

AU - Zonana, Jonathan (Jon)

AU - Kingman, Garrett A.

AU - Pers, Tune H.

AU - Baron, Jeffrey

AU - Rosenfeld, Ronald (Ron)

AU - Hirschhorn, Joel N.

AU - Harris, Matthew P.

AU - Hwa, Vivian

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