NPR2 encodes atrial natriuretic peptide receptor B (ANPRB), a regulator of skeletal growth. Biallelic 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).
Describe the physical proportions and growth characteristics of an extended family with novel NPR2 mutations including members with AMDM, ISS, or normal stature.
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.
The sisters with AMDM were compound heterozygotes for missense mutations in the NPR2 gene, a novel p.P93S (maternal) and the previously reported p.R989L (paternal). Both mutant ANPRB proteins were normally expressed in HEK293T cells and exhibited dominant negative effects on wild type ANPRB catalytic activity. 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 matured, while it remained constant in their wild type siblings.
Biallelic NPR2 mutations cause severe skeletal dysplasia (ADMD), whereas heterozygous mutations lead to a subtler phenotype characterized by progressive short stature characterized by increasing loss of height potential with age.

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