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PNAS Studies Describe Small-Cell Lung Model Mutations, CF Carrier Conditions, Joubert Modifier

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

Researchers at the Massachusetts Institute of Technology, Brigham and Women's Hospital, and Tufts University present a mouse model of small cell lung cancer (SCLC), developed with the help of gene editing. In an effort to find functionally relevant tumor suppressor gene candidates in the aggressive lung cancer subtype, the team used CRISPR -based gene editing to systematically introduce loss-of-function changes in genes flagged by prior sequencing analyses of SCLC — a search that highlighted enhanced tumor proliferation and progression in mice missing the p107 gene. "Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC," they report, "and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease."

A University of Iowa team takes a look at cystic fibrosis (CF)-related conditions in more than 19,800 individuals with mutations affecting just one copy of the CFTR gene, which is altered in an autosomal recessive manner in those with CF. For their retrospective population study, the researchers used de-identified health claims data to retrace treatments and diagnoses in tens of thousands of genotyped CF carriers, unaffected controls, and individuals with CF, uncovering higher-than-usual risk of pancreatitis, male infertility, diabetes, and other conditions in those with mutations affecting one copy of CFTR. "Although individual-level risk remained low for most conditions … population-level morbidity attributable to the CF carrier state is likely substantial," they suggest, noting that "[g]enetic testing may inform prevention, diagnosis, and treatment approaches for a broad range of CF carrier-related conditions."

Researchers from the UK, France, and the US describe an apparent modifier of cystic kidney disease in a mouse model of a ciliopathy condition called Joubert syndrome, which can be caused by alterations affecting both copies of a gene called CEP290. Using genotyped, CEP290-deficient mouse models from a mixed genetic background, the team searched for variants corresponding to cystic kidney features, focusing in on SNPs in and around a locus containing a BSND gene that codes for a chloride channel subunit called Barttin. When they dug into this region using exome sequence data for patients with CEP290 mutations, the authors saw signs that a common variant in BSND may modify kidney disease severity in humans with Joubert syndrome as well. "These findings make a significant contribution to the underplayed (and often ignored) role of genetic background in murine models," they note, "and how this can be exploited to understand further rare inherited disease."