Research

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

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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 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)

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