Supplemental Material for "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations"

Supplemental material, tables and figure for manuscript titled "Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations"

Abstract:

Background: NPR2 encodes natriuretic peptide receptor B (NPR-B), a regulator of skeletal growth. Homozygous loss-of-function mutations in NPR2 result in acromesomelic dysplasia Maroteaux type (AMDM; OMIM 602875), while heterozygous mutations may account for 2-6% of idiopathic short stature (ISS).

Objective: Describe the physical proportions and growth characteristics of an extended family with novel NPR2 mutations including members with AMDM, ISS, or normal stature.

Design and Participants: We performed whole exome sequencing in two healthy parents and two children with AMDM. Detailed genotyping and phenotyping was performed on members of a multigenerational family in an academic medical center. We expressed mutant proteins in mammalian cells and characterized expression and function.

Results: The sisters with AMDM were compound heterozygotes for two novel missense mutations in the NPR2 gene, p.P93S (maternal) and p.R989L (paternal), which lack catalytic function. Heterozygous relatives had proportionate short stature (height z-scores -2.06 ± 0.97, median ± SD) compared to their wild type siblings (-1.37 ± 0.59). Height z-scores progressively and significantly decreased as NPR2 heterozygous children aged, while it remained consistent in their wild type siblings.

Conclusions: Biallelic NPR2 mutations cause severe skeletal dysplasia (ADMD), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature and increasing loss of height potential with age.

Précis: Study of family including children with AMDM and short stature from novel NPR2 mutations. Subjects with heterozygous mutations showed progressive short stature and loss of height potential with age.