@article {1007,
	title = {De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.},
	journal = {Am J Hum Genet},
	volume = {108},
	year = {2021},
	month = {2021 02 04},
	pages = {357-367},
	abstract = {<p>Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28~{\texttimes} 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p~=~2.21~{\texttimes} 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.</p>},
	keywords = {Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Whole Exome Sequencing},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2021.01.008},
	author = {Weng, Patricia L and Majmundar, Amar J and Khan, Kamal and Lim, Tze Y and Shril, Shirlee and Jin, Gina and Musgrove, John and Wang, Minxian and Ahram, Dina F and Aggarwal, Vimla S and Bier, Louise E and Heinzen, Erin L and Onuchic-Whitford, Ana C and Mann, Nina and Buerger, Florian and Schneider, Ronen and Deutsch, Konstantin and Kitzler, Thomas M and Kl{\"a}mbt, Verena and Kolb, Amy and Mao, Youying and Moufawad El Achkar, Christelle and Mitrotti, Adele and Martino, Jeremiah and Beck, Bodo B and Altm{\"u}ller, Janine and Benz, Marcus R and Yano, Shoji and Mikati, Mohamad A and Gunduz, Talha and Cope, Heidi and Shashi, Vandana and Trachtman, Howard and Bodria, Monica and Caridi, Gianluca and Pisani, Isabella and Fiaccadori, Enrico and AbuMaziad, Asmaa S and Martinez-Agosto, Julian A and Yadin, Ora and Zuckerman, Jonathan and Kim, Arang and John-Kroegel, Ulrike and Tyndall, Amanda V and Parboosingh, Jillian S and Innes, A Micheil and Bierzynska, Agnieszka and Koziell, Ania B and Muorah, Mordi and Saleem, Moin A and Hoefele, Julia and Riedhammer, Korbinian M and Gharavi, Ali G and Jobanputra, Vaidehi and Pierce-Hoffman, Emma and Seaby, Eleanor G and O{\textquoteright}Donnell-Luria, Anne and Rehm, Heidi L and Mane, Shrikant and D{\textquoteright}Agati, Vivette D and Pollak, Martin R and Ghiggeri, Gian Marco and Lifton, Richard P and Goldstein, David B and Davis, Erica E and Hildebrandt, Friedhelm and Sanna-Cherchi, Simone}
}
@article {171,
	title = {Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.},
	journal = {Elife},
	volume = {4},
	year = {2015},
	month = {2015 Apr 24},
	pages = {e06315},
	abstract = {<p>Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5\%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.</p>},
	keywords = {Adolescent, Adult, Age of Onset, Aldosterone, Amino Acid Sequence, Calcium, Calcium Channels, T-Type, Calcium Signaling, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Hyperaldosteronism, Hypertension, Infant, Male, Membrane Potentials, Middle Aged, Molecular Sequence Data, Mutation, Phenotype, Recurrence, Sequence Alignment, Zona Glomerulosa},
	issn = {2050-084X},
	doi = {10.7554/eLife.06315},
	author = {Scholl, Ute I and St{\"o}lting, Gabriel and Nelson-Williams, Carol and Vichot, Alfred A and Choi, Murim and Loring, Erin and Prasad, Manju L and Goh, Gerald and Carling, Tobias and Juhlin, C Christofer and Quack, Ivo and Rump, Lars C and Thiel, Anne and Lande, Marc and Frazier, Britney G and Rasoulpour, Majid and Bowlin, David L and Sethna, Christine B and Trachtman, Howard and Fahlke, Christoph and Lifton, Richard P}
}
