Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature
| Autor: | Carolina Bezanilla-López, Miriam Aza-Carmona, Jimena Barraza-García, Maria Rodriguez-Zabala, Karen E. Heath, Antonio M. Lerario, Lucia Sentchordi, Alfonso Hisado-Oliva, Marta Alonso-Bernáldez, Alba Ruzafa-Martin, Sara Benito-Sanz, Mariana F A Funari, Angel Campos-Barros, Alexander A. L. Jorge |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Heterozygote Adolescent medicine.drug_class DNA Mutational Analysis Dwarfism Biology medicine.disease_cause Short stature 03 medical and health sciences Internal medicine Exome Sequencing medicine Natriuretic peptide Humans Amino Acid Sequence Achondroplasia Growth Charts Child Peptide sequence Genetics (clinical) Genes Dominant Mutation Computational Biology Natriuretic Peptide C-Type medicine.disease NPR2 Idiopathic short stature 030104 developmental biology Endocrinology Phenotype Female medicine.symptom |
| Zdroj: | Genetics in medicine : official journal of the American College of Medical Genetics. 20(1) |
| ISSN: | 1530-0366 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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