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Dev Cell 2016 Sep 12;385:478-92. doi: 10.1016/j.devcel.2016.08.002.
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Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.

Del Viso F , Huang F , Myers J , Chalfant M , Zhang Y , Reza N , Bewersdorf J , Lusk CP , Khokha MK .

Human genomics is identifying candidate genes for congenital heart disease (CHD), but discovering the underlying mechanisms remains challenging. In a patient with CHD and heterotaxy (Htx), a disorder of left-right patterning, we previously identified a duplication in Nup188. However, a mechanism to explain how a component of the nuclear pore complex (NPC) could cause Htx/CHD was undefined. Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact. Many data, including the localization of endogenous Nup188/93 at cilia bases, support their direct role at cilia. Super-resolution imaging of Nup188 shows two barrel-like structures with dimensions and organization incompatible with an NPC-like ring, arguing against a proposed "ciliary pore complex." We suggest that the nanoscale organization and function of nucleoporins are context dependent in a way that is required for the structure of the heart.

PubMed ID: 27593162
PMC ID: PMC5021619
Article link: Dev Cell
Grant support: [+]

Species referenced: Xenopus tropicalis
Genes referenced: actb arl13b cep290 dand5 foxj1 nup133 nup188 nup62 nup93 pitx2 rpe tuba4b tubg1
GO keywords: heart looping [+]
Antibodies: Nuclear Pore Complex Ab1 Tuba4b Ab5 Tubg1 Ab4
Morpholinos: nup133 MO1 nup188 MO1 nup62 MO1 nup93 MO1

Disease Ontology terms: visceral heterotaxy [+]
Phenotypes: Xtr Wt + Hsa.NUP188 (Fig. S 2 A) [+]

Article Images: [+] show captions
References [+] :
Alber, The molecular architecture of the nuclear pore complex. 2007, Pubmed