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

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

doi:10.1210/jc.2012-2150

Cited by 70 publications

(59 citation statements)

References 37 publications

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“…The genetic association of mutant ninein ( NIN ) and Cep215 ( CEP215 ) with microcephaly [27, 31] supports the idea that these proteins contribute to the phenotypes in MOPDII and the Pcnt −/− mouse through their loss from spindle poles in the absence of Pcnt. These results suggest that Pcnt may act as the core scaffold for such a complex during embryonic development.…”

Section: Resultsmentioning

confidence: 99%

A Unique Set of Centrosome Proteins Requires Pericentrin for Spindle-Pole Localization and Spindle Orientation

Chen

Hehnly

et al. 2014

Current Biology

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SUMMARY Majewski Osteodysplastic Primordial Dwarfism type II (MOPDII) is caused by mutations in the centrosome gene pericentrin (PCNT) which lead to severe pre- and post-natal growth retardation[1]. As in MOPDII patients, disruption of pericentrin (Pcnt) in mice caused a number of abnormalities including microcephaly, aberrant hemodynamics analyzed by in utero echocardiography and cardiovascular anomalies; the latter being associated with mortality, as in the human condition[1]. To identify the mechanisms underlying these defects, we tested for changes in cell and molecular function. All Pcnt−/− mouse tissues and cells examined showed spindle misorientation. This mouse phenotype was associated with misdirected ventricular septal growth in the heart, decreased proliferative symmetric divisions in brain neural progenitors and increased misoriented divisions in fibroblasts; the same phenotype was seen in fibroblasts from three MOPDII individuals. Misoriented spindles were associated with disrupted astral microtubules and near complete loss of a unique set of centrosome proteins from spindle poles (ninein, Cep215, centriolin). All these proteins appear to be crucial for microtubule anchoring and all interacted with Pcnt, suggesting that Pcnt serves as a molecular scaffold for this functionally-linked set of spindle pole proteins. Importantly, Pcnt disruption had no detectable effect on localization of proteins involved in the cortical polarity pathway (NuMA, p150glued, aPKC). Not only do these data reveal a spindle-pole-localized complex for spindle orientation, but they identify key spindle symmetry proteins involved in the pathogenesis of MOPDII.

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Section: Resultsmentioning

confidence: 99%

A Unique Set of Centrosome Proteins Requires Pericentrin for Spindle-Pole Localization and Spindle Orientation

Chen

Hehnly

et al. 2014

Current Biology

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“…Finally, we found sharply reduced staining for Ninein, another microcephaly-associated centrosomal protein 27 , at both the E14.5 mouse and E35 ferret ventricular surface (Fig. 4d, e).…”

Section: Main Textmentioning

confidence: 80%

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

Johnson

Sun

Kodani

et al. 2018

Nature

148

154

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The human cerebral cortex is distinguished by its large size and abundant gyrification, or folding, yet the evolutionary mechanisms driving cortical size and structure are unknown. While genes essential for cortical developmental expansion have been identified from the genetics of human primary microcephaly (“small head”, associated with reduced brain size and intellectual disability)1, studies of these genes in mice, whose smooth cortex is one thousand times smaller than that of humans, have provided limited insight. Mutations of abnormal spindle-like microcephaly-associated (ASPM), the most common recessive microcephaly gene, reduce cortical volume by ≥50% in humans2–4, but have little effect in mice5–9, likely reflecting evolutionarily divergent functions of ASPM10,11. We used genome editing to create a germline knockout (KO) of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell (NPC) diversity12–14 than mice, and closer Aspm protein sequence homology to human. Aspm KO ferrets exhibit severe microcephaly (25–40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as in human patients3,4, suggesting loss of “cortical units”. The mutant ferret fetal cortex displays a massive premature displacement of ventricular radial glial cells (VRG) to the outer subventricular zone (OSVZ), where many resemble outer radial glia (ORG), an NPC subtype essentially absent in mice and implicated in cerebral cortical expansion in primates12–16. These data suggest an evolutionary mechanism whereby Aspm regulates cortical expansion by controlling the affinity of VRG for the ventricular surface, thus modulating the ratio of VRG, the most undifferentiated cell type, to ORG, a more differentiated progenitor.

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“…In the past years, mutations in several genes have been identified in human microcephalic disorders, such as primary microcephaly (MCPH) and microcephalic primordial dwarfism (MPD). Many of the encoded proteins are involved in mitosis and centrosomal processes including centrosomal cohesion and integrity, maturation and assembly [Bond et al, 2002[Bond et al, , 2005Griffith et al, 2008;Rauch et al, 2008;Kumar et al, 2009;Bilg€ uvar et al, 2010;Nicholas et al, 2010;Yu et al, 2010;Kalay et al, 2011;Qvist et al, 2011;Sir et al, 2011;Dauber et al, 2012;Hussain et al, 2012;Khan et al, 2014;Martin et al, 2014;Shaheen et al, 2014]. It has been shown that alterations in the precisely orchestrated process of mitosis disturb the balance between symmetric and asymmetric cell division during embryonic neurogenesis and thereby lead to a decreased pool of progenitor cells, reduced neuronal proliferation, and, as a result, to reduced brain size [Fish et al, 2006;Zhong and Chia, 2008;Lancaster and Knoblich, 2012;Lancaster et al, 2013].…”

Section: Discussionmentioning

confidence: 99%

A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation

Yiğit

Wieczorek

Bögershausen

et al. 2015

American J of Med Genetics Pt A

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Using whole-exome sequencing, we identified a homozygous acceptor splice-site mutation in intron 6 of the KATNB1 gene in a patient from a consanguineous Turkish family who presented with congenital microcephaly, lissencephaly, short stature, polysyndactyly, and dental abnormalities. cDNA analysis revealed complete loss of the natural acceptor splice-site resulting either in the usage of an alternative, exonic acceptor splice-site inducing a frame-shift and premature protein truncation or, to a minor extent, in complete skipping of exon 7. Both effects most likely lead to complete loss of KATNB1 function. Homozygous and compound heterozygous mutations in KATNB1 have very recently been described as a cause of microcephaly with brain malformations and seizures. We extend the KATNB1 associated phenotype by describing a syndrome characterized by primordial dwarfism, lissencephaly, polysyndactyly, and dental anomalies, which is caused by a homozygous truncating KATNB1 mutation.

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

Cited by 70 publications

References 37 publications

A Unique Set of Centrosome Proteins Requires Pericentrin for Spindle-Pole Localization and Spindle Orientation

A Unique Set of Centrosome Proteins Requires Pericentrin for Spindle-Pole Localization and Spindle Orientation

Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size

A syndrome of microcephaly, short stature, polysyndactyly, and dental anomalies caused by a homozygous KATNB1 mutation

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