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

Autor(es):Mostrar menos -

Hisado-Oliva, Alfonso ^{[1, 2, 3]} ; Ruzafa-Martin, Alba ^[1] ; Sentchordi, Lucia ^{[1, 3, 4]} ; Funari, Mariana F. A. ^[5] ; Bezanilla-Lopez, Carolina ^[6] ; Alonso-Bernaldez, Marta ^[1] ; Barraza-Garcia, Jimena ^{[1, 2, 3]} ; Rodriguez-Zabala, Maria ^[1] ; Lerario, Antonio M. ^{[7, 8]} ; Benito-Sanz, Sara ^{[1, 2, 3]} ; Aza-Carmona, Miriam ^{[1, 2, 3]} ; Campos-Barros, Angel ^{[1, 2]} ; Jorge, Alexander A. L. ^{[5, 8]} ; Heath, Karen E. ^{[1, 2, 3]}

Afiliação do(s) autor(es)

^[1] Univ Autonoma Madrid, Hosp Univ La Paz, Inst Med & Mol Genet INGEMM, IdiPAZ, Madrid - Spain

^[2] Inst Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, U753, Madrid - Spain

^[3] Hosp Univ La Paz, Multidisciplinary Skeletal Dysplasia Unit UMDE, Madrid - Spain

^[4] Hosp Univ Infanta Leonor, Dept Pediat, Madrid - Spain

^[5] Univ Sao Paulo, Fac Med, Hosp Clin, Lab Hormonios & Genet Mol LIM42, Sao Paulo - Brazil

^[6] Hosp Univ Fdn Alcorcon, Dept Pediat, Madrid - Spain

^[7] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[8] Univ Sao Paulo, Fac Med, Unidade Endocrinol Genet LIM25, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Genetics in Medicine; v. 20, n. 1, p. 91-97, JAN 2018.
• Citações Web of Science: 17

Resumo

Purpose: C-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. Methods: NPPC 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. Results: Two 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. Conclusions: Our 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. (AU)

• Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
• Beneficiário: Alexander Augusto de Lima Jorge
• Modalidade de apoio: Auxílio à Pesquisa - Temático