Novel Microcephalic Primordial Dwarfism Disorder Associated with Variants in the Centrosomal Protein Ninein
Department of Stem Cell and Regenerative Biology (G.A.K.), Harvard University, Cambridge, Massachussetts 02138The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 08/2012; 97(11). DOI: 10.1210/jc.2012-2150
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.
Article: The New World of Clinical GenomicsThe Journal of Clinical Endocrinology and Metabolism 11/2012; 97(11):3912-4. DOI:10.1210/jc.2012-3288 · 6.21 Impact Factor
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ABSTRACT: Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) is an autosomal dominant skeletal dysplasia which is characterized by midface hypoplasia, short stature, joint laxity with dislocations, genua valga, progressive scoliosis, and slender fingers. Recently, heterozygous missense mutations in KIF22, a gene which encodes a member of the kinesin-like protein family, have been identified in sporadic as well as familial cases of SEMDJL2. In the present study homozygosity mapping and whole-exome sequencing were combined to analyse a consanguineous family with a phenotype resembling SEMDJL2. We identified homozygous missense mutations in the two nearby genes NIN (Ninein) and POLE2 (DNA polymerase epsilon subunit B) which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. We present several lines of evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The centrosomal protein NIN shows a functional relationship with KIF22 and other proteins associated with chromosome congression/movement, centrosomal function, and ciliogenesis, which have been associated with skeletal dysplasias. Moreover, compound heterozygous missense mutations at more N-terminal positions of Ninein have very recently been identified in a family with microcephalic primordial dwarfism. Together with the present report this strongly supports a fundamental role of Ninein in skeletal development.Matrix biology: journal of the International Society for Matrix Biology 05/2013; 32(7). DOI:10.1016/j.matbio.2013.05.001 · 5.07 Impact Factor
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ABSTRACT: Microcephaly represents one of the most obvious clinical manifestations of impaired neurogenesis. Defects in the DNA damage response, in DNA repair, and structural abnormalities in centrosomes, centrioles and the spindle microtubule network have all been demonstrated to cause microcephaly in humans. Work describing novel functional defects in cell lines from individuals with either Meier-Gorlin syndrome or Wolf-Hirschhorn syndrome highlight the significance of optimal DNA replication and S phase progression for normal human development, including neurogenesis. These findings illustrate how different primary defects in processes impacting upon DNA replication potentially influence similar phenotypic outcomes, including growth retardation and microcephaly. Herein, we will describe the nature of the S phase defects uncovered for each of these conditions and highlight some of the overlapping cellular features.DNA repair 05/2013; 12(8). DOI:10.1016/j.dnarep.2013.04.016 · 3.11 Impact Factor
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