The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects
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The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects. / Gripp, Karen W; Baker, Laura; Robbins, Katherine M; Stabley, Deborah L; Bellus, Gary A; Kolbe, Verena; Nauth, Theresa; Rosenberger, Georg.
in: EUR J HUM GENET, Jahrgang 28, Nr. 11, 11.2020, S. 1548-1554.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects
AU - Gripp, Karen W
AU - Baker, Laura
AU - Robbins, Katherine M
AU - Stabley, Deborah L
AU - Bellus, Gary A
AU - Kolbe, Verena
AU - Nauth, Theresa
AU - Rosenberger, Georg
PY - 2020/11
Y1 - 2020/11
N2 - Specific activating missense HRAS variants cause Costello syndrome (CS), a RASopathy with recognizable facial features. The majority of these dominant disease causing variants affect the glycine residues in position 12 or 13. A clinically suspected CS diagnosis can be confirmed through identification of a dominant pathogenic HRAS variant. A novel HRAS variant predicting p.(Glu62_Arg68dup) was identified in an individual with hypertrophic cardiomyopathy, Chiari 1 malformation and ectodermal findings consistent with a RASopathy. Functional studies showed that the p.Glu62_Arg68dup alteration affects HRAS interaction with effector protein PIK3CA (catalytic subunit of phosphoinositide 3-kinase) and the regulator neurofibromin 1 (NF1) GTPase-activating protein (GAP). HRASGlu62_Arg68dup binding with effectors rapidly accelerated fibrosarcoma (RAF1), RAL guanine nucleotide dissociation stimulator (RALGDS) and phospholipase C1 (PLCE1) was enhanced. Accordingly, p.Glu62_Arg68dup increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF1, whereas AKT phosphorylation downstream of PI3K was not significantly affected. Growth factor stimulation revealed that expression of HRASGlu62_Arg68dup abolished the HRAS' capacity to modulate downstream signaling. Our data underscore that different qualities of dysregulated HRAS-dependent signaling dynamics determine the clinical severity in CS.
AB - Specific activating missense HRAS variants cause Costello syndrome (CS), a RASopathy with recognizable facial features. The majority of these dominant disease causing variants affect the glycine residues in position 12 or 13. A clinically suspected CS diagnosis can be confirmed through identification of a dominant pathogenic HRAS variant. A novel HRAS variant predicting p.(Glu62_Arg68dup) was identified in an individual with hypertrophic cardiomyopathy, Chiari 1 malformation and ectodermal findings consistent with a RASopathy. Functional studies showed that the p.Glu62_Arg68dup alteration affects HRAS interaction with effector protein PIK3CA (catalytic subunit of phosphoinositide 3-kinase) and the regulator neurofibromin 1 (NF1) GTPase-activating protein (GAP). HRASGlu62_Arg68dup binding with effectors rapidly accelerated fibrosarcoma (RAF1), RAL guanine nucleotide dissociation stimulator (RALGDS) and phospholipase C1 (PLCE1) was enhanced. Accordingly, p.Glu62_Arg68dup increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF1, whereas AKT phosphorylation downstream of PI3K was not significantly affected. Growth factor stimulation revealed that expression of HRASGlu62_Arg68dup abolished the HRAS' capacity to modulate downstream signaling. Our data underscore that different qualities of dysregulated HRAS-dependent signaling dynamics determine the clinical severity in CS.
U2 - 10.1038/s41431-020-0662-4
DO - 10.1038/s41431-020-0662-4
M3 - SCORING: Journal article
C2 - 32499600
VL - 28
SP - 1548
EP - 1554
JO - EUR J HUM GENET
JF - EUR J HUM GENET
SN - 1018-4813
IS - 11
ER -