NPR2 – Acromesomelic Dysplasia, Maroteaux Type

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare autosomal recessive skeletal dysplasia caused by biallelic mutations in NPR2, encoding natriuretic peptide receptor B. Affected individuals present with severe disproportionate shortening of the middle and distal segments of the limbs, vertebral body wedging, and normal intelligence, defining a distinctive phenotypic signature for Acromesomelic Dysplasia, Maroteaux Type.

Genetic studies have identified 19 unrelated probands with AMDM harboring homozygous or compound heterozygous NPR2 variants, including nonsense, frameshift, splice-site, and missense mutations. These alleles segregate in three consanguineous families (PMID:25959430) and have been reported across multiple ethnicities over nearly two decades (PMID:26349192; PMID:35368703; PMID:34162036).

The variant spectrum comprises at least 25 unique alleles: 8 nonsense, 6 frameshift, 4 splice-site, and 7 missense changes. The recurrent nonsense mutation c.1435C>T (p.Arg479Ter) truncates the guanylyl cyclase domain and abolishes receptor function in patient fibroblasts and in vitro assays (PMID:26349192).

Functional assays consistently demonstrate loss of guanylyl cyclase activity. Initial characterization of 21 AMDM families revealed multiple LoF alleles with markedly deficient cGMP production in HEK293 cells for three tested missense variants (PMID:15146390). More recent work confirmed that c.1112G>A (p.Arg371Gln) and c.2887+2T>C disrupt ligand binding and homodimer formation, leading to negligible catalytic output (PMID:35368703).

Mechanistically, biallelic LoF in NPR2 abolishes C-type natriuretic peptide–mediated cGMP signaling, impairing chondrocyte proliferation and endochondral ossification. Heterozygous carriers manifest milder, proportionate short stature without skeletal deformities, reflecting a dose-dependent haploinsufficiency effect (PMID:15146390).

Collectively, the breadth of genetic and experimental evidence meets ClinGen criteria for a definitive gene–disease association. Clinical testing of NPR2 is recommended in patients with disproportionate acromesomelic shortening, and validated functional assays provide robust variant interpretation and support therapeutic decision-making.

References

• Genetic counseling (Geneva, Switzerland) • 2015 • A NOVEL MUTATION IN NPR2 GENE IN A PATIENT WITH ACROMESOMELIC DYSPLASIA, MAROTEAUX TYPE. PMID:26349192
• Annals of Human Genetics • 2015 • Homozygous sequence variants in the NPR2 gene underlying Acromesomelic dysplasia Maroteaux type (AMDM) in consanguineous families. PMID:25959430
• American Journal of Human Genetics • 2004 • Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. PMID:15146390
• Frontiers in Genetics • 2022 • Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type. PMID:35368703
• Journal of Pediatric Endocrinology & Metabolism • 2021 • Acromesomelic dysplasia-Maroteaux type, nine patients with two novel NPR2 variants. PMID:34162036

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