Novel Microcephalic Primordial Dwarfism Disorder Associated with Variants in the Centrosomal Protein Ninein

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

    Research output: Contribution to journalJournal articleResearchpeer-review

    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 pro-bands were compound heterozygotes. In the zebrafish, ninein knock down 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. (J Clin Endocrinol Metab 97: E2140-E2151, 2012)
    Original languageEnglish
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume97
    Issue number11
    Pages (from-to)E2140-E2151
    ISSN0021-972X
    DOIs
    Publication statusPublished - 2012

    Keywords

    • Pisces Vertebrata Chordata Animalia (Animals, Chordates, Fish, Nonhuman Vertebrates, Vertebrates) - Osteichthyes [85206] zebrafish common
    • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common adolescent, adult female Indian
    • human NIN gene [Hominidae] human ninein gene missense mutation
    • morpholino oligonucleotide
    • ninein mutation, centrosomal protein
    • 03502, Genetics - General
    • 03506, Genetics - Animal
    • 03508, Genetics - Human
    • 07004, Behavioral biology - Human behavior
    • 17002, Endocrine - General
    • 18004, Bones, joints, fasciae, connective and adipose tissue - Physiology and biochemistry
    • 18006, Bones, joints, fasciae, connective and adipose tissue - Pathology
    • 20504, Nervous system - Physiology and biochemistry
    • 21002, Psychiatry - Psychopathology, psychodynamics and therapy
    • 25000, Pediatrics
    • 25503, Development and Embryology - Pathology
    • Clinical Endocrinology
    • Medical Genetics
    • Molecular Genetics
    • Orthopedics
    • asymmetric cell division
    • brain development
    • functional study
    • molecular study
    • morphogenesis
    • skull development
    • intellectual disability behavioral and mental disorders
    • microcephalic primordial dwarfism disorder MPD congenital disease, endocrine disease, genetic disease, bone disease etiology, genetics
    • Allied Medical Sciences
    • Biochemistry and Molecular Biophysics
    • Human Medicine, Medical Sciences
    • anterior neuroectoderm nervous system
    • brain nervous system
    • cranium
    • primary fibroblast
    • skull skeletal system
    • whole-exome sequencing laboratory techniques, genetic techniques

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