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Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

ABSTRACT: 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.

SUBMITTER: Tenney AP 

PROVIDER: S-EPMC10335940 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Tenney Alan P AP   Di Gioia Silvio Alessandro SA   Webb Bryn D BD   Chan Wai-Man WM   de Boer Elke E   Garnai Sarah J SJ   Barry Brenda J BJ   Ray Tammy T   Kosicki Michael M   Robson Caroline D CD   Zhang Zhongyang Z   Collins Thomas E TE   Gelber Alon A   Pratt Brandon M BM   Fujiwara Yuko Y   Varshney Arushi A   Lek Monkol M   Warburton Peter E PE   Van Ryzin Carol C   Lehky Tanya J TJ   Zalewski Christopher C   King Kelly A KA   Brewer Carmen C CC   Thurm Audrey A   Snow Joseph J   Facio Flavia M FM   Narisu Narisu N   Bonnycastle Lori L LL   Swift Amy A   Chines Peter S PS   Bell Jessica L JL   Mohan Suresh S   Whitman Mary C MC   Staffieri Sandra E SE   Elder James E JE   Demer Joseph L JL   Torres Alcy A   Rachid Elza E   Al-Haddad Christiane C   Boustany Rose-Mary RM   Mackey David A DA   Brady Angela F AF   Fenollar-Cortés María M   Fradin Melanie M   Kleefstra Tjitske T   Padberg George W GW   Raskin Salmo S   Sato Mario Teruo MT   Orkin Stuart H SH   Parker Stephen C J SCJ   Hadlock Tessa A TA   Vissers Lisenka E L M LELM   van Bokhoven Hans H   Jabs Ethylin Wang EW   Collins Francis S FS   Pennacchio Len A LA   Manoli Irini I   Engle Elizabeth C EC  

Nature genetics 20230629 7

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  ...[more]

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