Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.
Alan P TenneySilvio Alessandro Di GioiaBryn D WebbWai-Man ChanElke de BoerSarah J GarnaiBrenda J BarryTammy RayMichael KosickiCaroline D RobsonZhongyang ZhangThomas E CollinsAlon GelberBrandon M PrattYuko FujiwaraArushi VarshneyMonkol LekPeter E WarburtonCarol Van RyzinTanya J LehkyChristopher ZalewskiKelly A KingCarmen C BrewerAudrey ThurmJoseph SnowFlavia M FacioNarisu NarisuLori L BonnycastleAmy SwiftPeter S ChinesJessica L BellSuresh MohanMary C WhitmanSandra E StaffieriJames E ElderJoseph L DemerAlcy TorresElza RachidChristiane Al-HaddadRose-Mary N BoustanyDavid A MackeyAngela F BradyMaría Fenollar-CortésMelanie FradinTjitske KleefstraGeorge W PadbergSalmo RaskinMario Teruo SatoStuart H OrkinStephen C J ParkerTessa A HadlockLisenka E L M VissersHans van BokhovenEthylin Wang JabsFrancis S CollinsLen A PennacchioIrini ManoliElizabeth C EnglePublished in: Nature genetics (2023)
Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.