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Dr.Nat.Med. Arwa Ishaq Khayyat

Assistant Professor

عضو هيئة تدريس

كلية العلوم
Building 5, Third Floor, Office 226
المنشورات
مقال فى مجلة
2018

Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome: J Clin Invest.

Khayyat, Arwa Ishaq A . 2018

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107NUP85NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

رقم المجلد
10.1172/JCI98688
مجلة/صحيفة
J Clin Invest. Oct 1;128(10):4313-4328. doi: 10.1172/JCI98688. Epub 2018 Sep 4
الصفحات
4313-4328
مزيد من المنشورات
publications

Jawad syndrome (JWDS) (MIM #251255) is a multiple congenital anomaly and intellectual disability (ID) syndrome characterized by congenital microcephaly, facial dysmorphism, digital anomalies,…

بواسطة Arwa Ishaq A Khayyat
2021
publications

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS…

بواسطة Arwa Ishaq A Khayyat
2018