title: Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes.
abstract: Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4α). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4α in both lymphoblasts and pancreatic β-cells, including compounds that physically interact with HNF4α. Compounds including US Food and Drug Administration-approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from β-cells. This method may suggest therapeutic hypotheses for other nonblood disorders.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. shaw.stanley@mgh.harvard.edu
authors.forename: Stanley Y
authors.initials: SY
authors.lastname: Shaw
authors.forename: David M
authors.initials: DM
authors.lastname: Blodgett
authors.forename: Maggie S
authors.initials: MS
authors.lastname: Ma
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Westly
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000483:Alleles; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000473:pathology*; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D000255:Adenosine Triphosphate; D005947:Glucose