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However, the underlying mechanisms remain poorly understood, and little is known about the impact of LQTS-associated mutations. We show that 17\n            <jats:inline-formula>\n              <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                <mml:mo>$<\/mml:mo>\n                <mml:mi>\u03b2<\/mml:mi>\n                <mml:mo>$<\/mml:mo>\n              <\/mml:math>\n            <\/jats:inline-formula>\n            -E2 inhibits the human cardiac Kv7.1\/KCNE1 channel expressed in\n            <jats:italic>Xenopus<\/jats:italic>\n            oocytes. We find that the 17\n            <jats:inline-formula>\n              <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                <mml:mo>$<\/mml:mo>\n                <mml:mi>\u03b2<\/mml:mi>\n                <mml:mo>$<\/mml:mo>\n              <\/mml:math>\n            <\/jats:inline-formula>\n            -E2 effect depends on the Kv7.1 to KCNE1 stoichiometry, and we reveal a critical function of the KCNE1 carboxyl terminus for the effect. LQTS-associated mutations in the KCNE1 carboxyl terminus show a range of responses to 17\n            <jats:inline-formula>\n              <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                <mml:mo>$<\/mml:mo>\n                <mml:mi>\u03b2<\/mml:mi>\n                <mml:mo>$<\/mml:mo>\n              <\/mml:math>\n            <\/jats:inline-formula>\n            -E2, from a wild-type like response to impaired or abolished response. Together, this study increases our understanding of the mechanistic basis for 17\n            <jats:inline-formula>\n              <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                <mml:mo>$<\/mml:mo>\n                <mml:mi>\u03b2<\/mml:mi>\n                <mml:mo>$<\/mml:mo>\n              <\/mml:math>\n            <\/jats:inline-formula>\n            -E2 inhibition of Kv7.1\/KCNE1 and demonstrates mutation-dependent responses to 17\n            <jats:inline-formula>\n              <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                <mml:mo>$<\/mml:mo>\n                <mml:mi>\u03b2<\/mml:mi>\n                <mml:mo>$<\/mml:mo>\n              <\/mml:math>\n            <\/jats:inline-formula>\n            -E2. These findings suggest that the 17\n            <jats:inline-formula>\n              <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                <mml:mo>$<\/mml:mo>\n                <mml:mi>\u03b2<\/mml:mi>\n                <mml:mo>$<\/mml:mo>\n              <\/mml:math>\n            <\/jats:inline-formula>\n            -E2 effect on Kv7.1\/KCNE1 might contribute to the higher arrhythmia risk of women, particularly in carriers with specific LQTS-associated mutations.\n          <\/jats:p>","DOI":"10.1126\/sciadv.ade7109","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T17:58:42Z","timestamp":1678903122000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Long-QT mutations in KCNE1 modulate the 17\u03b2-estradiol response of 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