Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.
Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.
['Muir|Alison M|AM|', 'Cohen|Jennifer L|JL|', 'Sheppard|Sarah E|SE|', 'Guttipatti|Pavithran|P|', 'Lo|Tsz Y|TY|', 'Weed|Natalie|N|', 'Doherty|Dan|D|', 'DeMarzo|Danielle|D|', 'Fagerberg|Christina R|CR|', 'Kjærsgaard|Lars|L|', 'Larsen|Martin J|MJ|', 'Rump|Patrick|P|', 'Löhner|Katharina|K|', 'Hirsch|Yoel|Y|', 'Zeevi|David A|DA|', 'Zackai|Elaine H|EH|', 'Bhoj|Elizabeth|E|', 'Song|Yuanquan|Y|', 'Mefford|Heather C|HC|']
D021581:Active Transport, Cell Nucleus D000483:Alleles D000818:Animals D001921:Brain D002467:Cell Nucleus D002675:Child, Preschool D003712:Dendrites D029721:Drosophila Proteins D004331:Drosophila melanogaster D005124:Eye Abnormalities D005260:Female D005347:Fibroblasts D005808:Genes, Recessive D006330:Heart Defects, Congenital D006801:Humans D007223:Infant D007231:Infant, Newborn D007585:Jews D000073658:Loss of Function Mutation D008297:Male D028861:Nuclear Pore Complex Proteins D012640:Seizures D013577:Syndrome D028961:beta Karyopherins
NUP188 nucleoporin congenital cataracts congenital heart defects Ashkenazi Jewish autosomal recessive dendritic arborization microcephaly negative geotaxis nuclear pore complex