Monday, November 18, 2019

Drosophila study contributes to understanding molecular mechanisms related to Zika virus-associated microcephaly

Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly

Nichole Link, Hyunglok Chung, Angad Jolly, Ghayda M. Mirzaa, James R. Lupski, Hugo J. Bellen
Published:November 14, 2019

Summary: "The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division."

Fly studies contribute to understanding of novel monogenic cause of steroid-resistance nephrotic syndrome

Kampf LL, Schneider R, Gerstner L, Thünauer R, Chen M, Helmstädter M, Amar A, Onuchic-Whitford AC, Loza Munarriz R, Berdeli A, Müller D, Schrezenmeier E, Budde K, Mane S, Laricchia KM, Rehm HL, MacArthur DG, Lifton RP, Walz G, Römer W, Bergmann C, Hildebrandt F, Hermle T. TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome. J Am Soc Nephrol. 2019 Nov 15. pii: ASN.2019040414. doi: 10.1681/ASN.2019040414. PMID: 31732614.

From the abstract: "Mutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. ... We used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes ..."

Monday, November 4, 2019

Experiments in Drosophila contribute to study of human gene variants associated with an early onset epileptic encephalopathy

Suzuki H, Yoshida T, Morisada N, Uehara T, Kosaki K, Sato K, Matsubara K, Takano-Shimizu T, Takenouchi T. De novo NSF mutations cause early infantile epileptic encephalopathy. Ann Clin Transl Neurol. 2019 Nov 1. doi: 10.1002/acn3.50917. PubMed PMID: 31675180.

Abstract: "N-ethylmaleimide-sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy."