Novel Microcephalic Primordial Dwarfism Disorder Associated with Variants in the Centrosomal Protein Ninein
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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ABSTRACT: Background/Aims: In addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature. Methods: Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information. Results: CNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature. Conclusion: SNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes. © 2014 S. Karger AG, Basel.Hormone Research in Paediatrics 10/2014; DOI:10.1159/000367712 · 1.71 Impact Factor
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ABSTRACT: Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH-IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH-IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH-IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome.International Journal of Pediatric Endocrinology 11/2013; 2013(1):19. DOI:10.1186/1687-9856-2013-19
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ABSTRACT: Otoconia are bio-crystals which couple mechanic forces to the sensory hair cells in the utricle and saccule, a process essential for us to sense linear acceleration and gravity for the purpose of maintaining bodily balance. In fish, structurally similar bio-crystals called otoliths mediate both balance and hearing. Otoconia abnormalities are common and can cause vertigo and imbalance in humans. However, the molecular etiology of these illnesses is unknown, as investigators have only begun to identify genes important for otoconia formation in recent years. To date, in-depth studies of selected mouse otoconial proteins have been performed, and about 75 zebrafish genes have been identified to be important for otolith development. This review will summarize recent findings as well as compare otoconia and otolith development. It will provide an updated brief review of otoconial proteins along with an overview of the cells and cellular processes involved. While continued efforts are needed to thoroughly understand the molecular mechanisms underlying otoconia and otolith development, it is clear that the process involves a series of temporally and spatially specific events that are tightly coordinated by numerous proteins. Such knowledge will serve as the foundation to uncover the molecular causes of human otoconia-related disorders. Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc.Developmental Dynamics 03/2015; 244(3). DOI:10.1002/dvdy.24195 · 2.67 Impact Factor