Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature
Author
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Wang, Sophie
Author
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Jacobsen, Christina
Author
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Carmichael, Heather
Author
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Edmund, Aaron
Author
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Robinson, Jerid
Author
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Olney, Robert
Author
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Miller, Timothy C.
Author
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Moon, Jennifer E.
Author
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Mericq, Verónica
Author
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Potter, Lincoln R.
Author
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Warman, Matthew L.
Author
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Hirschhorn, Joel N.
Author
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Dauber, Andrew
Admission date
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2015-07-09T19:17:50Z
Available date
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2015-07-09T19:17:50Z
Publication date
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2015
Cita de ítem
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Human Mutation, Vol. 36, No. 4, 474–481, 2015
en_US
Identifier
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DOI: 10.1002/humu.22773
Identifier
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https://repositorio.uchile.cl/handle/2250/131902
General note
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Artículo de publicación ISI
en_US
Abstract
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Based on the observation of reduced stature
in relatives of patients with acromesomelic dysplasia,
Maroteaux type (AMDM), caused by homozygous or
compound heterozygous mutations in natriuretic peptide
receptor-B gene (NPR2), it has been suggested that heterozygous
mutations in this gene could be responsible for
the growth impairment observed in some cases of idiopathic
short stature (ISS). We enrolled 192 unrelated
patients with short stature and 192 controls of normal
height and identified seven heterozygous NPR2 missense
or splice site mutations all in the short stature patients,
including one de novo splice site variant. Three of the
six inherited variants segregated with short stature in the
family. Nine additional rare nonsynonymous NPR2 variants
were found in three additional cohorts. Functional
studies identified eight loss-of-function mutations in short
individuals and one gain-of-function mutation in tall individuals.
With these data, we were able to rigorously verify
that NPR2 functional haploinsufficiency contributes to
short stature. We estimate a prevalence of NPR2 haploinsufficiency
of between 0 and 1/26 in people with ISS.