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Genet Med. 2018 Jan;20(1):91-97. doi: 10.1038/gim.2017.66. Epub 2017 Jun 28.

Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature.

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Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, U753), Instituto Carlos III, Madrid, Spain.
Multidisciplinary Skeletal Dysplasia Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Department of Pediatrics, Hospital Universitario Infanta Leonor, Madrid, Spain.
Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
Department of Pediatrics, Hospital Universitario Fundación Alcorcón, Madrid, Spain.
Unidade de Endocrinologia Genetica (LIM25), Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, Brazil.
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.


PurposeC-type natriuretic peptide (CNP) and its principal receptor, natriuretic peptide receptor B (NPR-B), have been shown to be important in skeletal development. CNP and NPR-B are encoded by natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor 2 (NPR2) genes, respectively. While NPR2 mutations have been described in patients with skeletal dysplasias and idiopathic short stature (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, no mutations in NPPC have been described in patients to date.MethodsNPPC was screened in 668 patients (357 with disproportionate short stature and 311 with autosomal dominant ISS) and 29 additional ISS families in an ongoing whole-exome sequencing study.ResultsTwo heterozygous NPPC mutations, located in the highly conserved CNP ring, were identified. Both showed significant reductions in cyclic guanosine monophosphate synthesis, confirming their pathogenicity. Interestingly, one has been previously linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant.ConclusionsOur results demonstrate, for the first time, that NPPC mutations cause autosomal dominant short stature in humans. The NPPC mutations cosegregated with a short stature and small hands phenotype. A CNP analog, which is currently in clinical trials for the treatment of achondroplasia, seems a promising therapeutic approach, since it directly replaces the defective protein.

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