bims-bicyki 2023-06-11 papers

Indian J Dermatol. 2023 Mar-Apr;68(2):68(2): 200-204

Tuberous Sclerosis Complex-Varied Presentations in Family Clusters.

Ayush Sopori, Seema Sharma, Kavya Sharma, Milap Sharma.

Tuberous sclerosis complex (TSC) is a disease of varying presentations characterised by the presence of multiple hamartomas in various organ systems in the body. This is an Autosomal dominant disease with damages in two suppressor genes namely TSC1 and TSC2 located on chromosome 9 (9q34-hamartin) and chromosome 16 (16p13.3-tuberin). It is a lifelong disease with neurological manifestations, for example, epilepsy, mental retardation and autism and major dermatological features like facial fibromas (adenoma sebaceum), periungual fibromas, shagreen patches and hypopigmented macules. Some conditions, for example, autosomal dominant polycystic kidney disease can co-exist with TSC as a result of concurrent deletion of both polycystic kidney disease 1 and TSC2 genes present on chromosome 16p13.3. We present a cluster of three families with TSC having varied presentations.

Keywords: Angiofibroma; ash leaf macules; rhabdomyoma

DOI: https://doi.org/10.4103/ijd.IJD_706_20

Exp Cell Res. 2023 Jun 03. pii: S0014-4827(23)00218-5. [Epub ahead of print] 113671

Increase in primary cilia number and length upon VDAC1 depletion contributes to attenuated proliferation of cancer cells.

Arpita Dutta, Priyadarshini Halder, Anakshi Gayen, Avik Mukherjee, Chandrama Mukherjee, Shubhra Majumder.

Primary cilia (PCs) that are present in most human cells and perform sensory function or signal transduction are lost in many solid tumors. Previously, we identified VDAC1, best known to regulate mitochondrial bioenergetics, to negatively regulate ciliogenesis. Here, we show that downregulation of VDAC1 in pancreatic cancer-derived Panc1 and glioblastoma-derived U-87MG cells significantly increased ciliation. Those PCs were significantly longer than the control cells. Such increased ciliation possibly inhibited cell cycle, which contributed to reduced proliferation of these cells. VDAC1-depletion also led to longer PCs in quiescent RPE1 cells. Therefore, serum-induced PC disassembly was slower in VDAC1-depleted RPE1 cells. Overall, this study reiterates the importance of VDAC1 in modulating tumorigenesis, due to its novel role in regulating PC disassembly and cilia length.

Keywords: Cell cycle; Cilia disassembly; Mitochondria; Primary cilia; Proliferation; Tumorigenesis; VDAC1

DOI: https://doi.org/10.1016/j.yexcr.2023.113671

Mol Genet Genomic Med. 2023 Jun 05. e2217

A novel heterozygous PKD1 variant causing alternative splicing in a Chinese family with autosomal dominant polycystic kidney disease.

Qianying Zhao, Yu Tan, Xiao Xiao, Qinqin Xiang, Mei Yang, He Wang, Shanling Liu.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by pathogenic variants of PKD1 and PKD2. Compared to PKD2-related patients, patients with PKD1 pathogenic variants have more severe symptoms, present a gradual decline in renal function, and finally progress to end-stage kidney disease with an earlier mean onset age.
METHODS: In this study, trio exome sequencing (ES) was performed to reveal the genetic etiology in a Chinese family clinically diagnosed with polycystic kidney, followed by validation through Sanger sequencing on both genomic DNA and cDNA levels. Subsequently, targeted preimplantation genetic testing was provided for the family.
RESULTS: A novel heterozygous PKD1 variant (c.1717_1722+11del) was detected in the proband and other clinically-affected relatives. Interestingly, cDNA sequencing demonstrated that the variant, despite being annotated as non-frameshift within exon 8, impacted the splicing of PKD1. Two abnormal transcription products were formed: one induced frameshift, while the other caused 133 amino acids to be inserted between exon 8 and exon 9.
CONCLUSIONS: Our study revealed a novel PKD1 variant using ES as the cause of ADPKD in a Chinese family with multiple affected members. The variant at the exon-intron boundary would induce alternative splicing, which should not be excluded from genetic analysis. Validated on the cDNA level could provide more comprehensive genetic information for disease stratification. And the novel variant expands the spectrum of PKD1 variants in ADPKD. The recurrent risk could be blocked accordingly for the families' offspring.

Keywords: PKD1 ; alternative splicing; autosomal dominant polycystic kidney disease (ADPKD); exome sequencing (ES)

DOI: https://doi.org/10.1002/mgg3.2217

MicroPubl Biol. 2023 ;2023

The C. elegans deglutamylase CCPP-6 does not operate redundantly with CCPP-1 in gross cilia integrity.

Abigail S Klimas, Jessica Dominguez, Bhumi P Shah, Zion Y Lee, Nina Peel.

Tubulin glutamylation is a reversible modification of the microtubules that regulates cilia stability and function. The addition of glutamates to the microtubule is catalyzed by members of the TTLL family of enzymes, while the removal is carried out by a family of cytosolic carboxypeptidase (CCP) enzymes. C. elegans has two deglutamylating enzymes, CCPP-1 and CCPP-6 . CCPP-1 is required for ciliary stability and function in the worm, however CCPP-6 is dispensable for cilia integrity. To investigate redundancy between the two deglutamylating enzymes we made a ccpp-1 ( ok1821 ); ccpp-6 ( ok382 ) double mutant. The double mutant shows normal viability, and the dye-filling phenotypes are not worse than the ccpp-1 single mutant, suggesting that CCPP-1 and CCPP-6 do not function redundantly in C. elegans cilia .

DOI: https://doi.org/10.17912/micropub.biology.000740

bioRxiv. 2023 May 24. pii: 2023.05.23.540554. [Epub ahead of print]

GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.

Nicholas Hoppe, Simone Harrison, Sun-Hee Hwang, Ziwei Chen, Masha Karelina, Ishan Deshpande, Carl-Mikael Suomivuori, Vivek R Palicharla, Samuel P Berry, Philipp Tschaikner, Dominik Regele, Douglas F Covey, Eduard Stefan, Debora S Marks, Jeremy Reiter, Ron O Dror, Alex S Evers, Saikat Mukhopadhyay, Aashish Manglik.

The orphan G protein-coupled receptor (GPCR) GPR161 is enriched in primary cilia, where it plays a central role in suppressing Hedgehog signaling 1 . GPR161 mutations lead to developmental defects and cancers 2,3,4 . The fundamental basis of how GPR161 is activated, including potential endogenous activators and pathway-relevant signal transducers, remains unclear. To elucidate GPR161 function, we determined a cryogenic-electron microscopy structure of active GPR161 bound to the heterotrimeric G protein complex G s . This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, we identify a sterol that binds to a conserved extrahelical site adjacent to transmembrane helices 6 and 7 and stabilizes a GPR161 conformation required for G s coupling. Mutations that prevent sterol binding to GPR161 suppress cAMP pathway activation. Surprisingly, these mutants retain the ability to suppress GLI2 transcription factor accumulation in cilia, a key function of ciliary GPR161 in Hedgehog pathway suppression. By contrast, a protein kinase A-binding site in the GPR161 C-terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how unique structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the broader role of GPR161 function in other signaling pathways.

DOI: https://doi.org/10.1101/2023.05.23.540554