Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis
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...
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Veröffentlicht in: | Nature genetics 2023-07, Vol.55 (7), p.1149-1163 |
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Sprache: | eng |
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Zusammenfassung: | 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.
GATA2
regulatory mutations are associated with hereditary congenital facial paresis in humans. A genetically engineered mouse model recapitulates the human phenotype, showing altered neuron-specific
Gata2
expression and a bias in formation of inner-ear efferent neurons over facial branchial motor neurons. |
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ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/s41588-023-01424-9 |