An Activating Mutation in the Kinase Homology Domain of the Natriuretic Peptide Receptor-2 Causes Extremely Tall Stature Without Skeletal Deformities

Hannema, Sabine E.; Duyvenvoorde, Hermine A. van; Premsler, Thomas; Yang, Ruey‐Bing; Mueller, Thomas D.; Gaßner, Birgit; Oberwinkler, Heike; Roelfsema, Ferdinand; Santen, Gijs W.E.; Prickett, Timothy C. R.; Kant, Sarina G.; Verkerk, Annemieke J.M.H.; Uitterlinden, André G.; Espiner, Eric A.; Ruivenkamp, Claudia; Oostdijk, Wilma; Pereira, Alberto M; Losekoot, Monique; Kühn, Michaela; Wit, Jan M.

doi:10.1210/jc.2013-2358

Cited by 83 publications

(89 citation statements)

References 42 publications

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“…Recently, heterozygous loss-of-function mutations in NPR2 have been implicated as a cause of short stature in patients initially classified as having idiopathic short stature [16,17]. Conversely, some studies have pointed heterozygous gain-of-function mutations in NPR2 as a cause of tall stature [18,19,20]. A similar phenotype had been observed in an individual with overexpression of the CNP caused by a balanced translocation [21,22].…”

Section: Introductionmentioning

confidence: 93%

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Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

Vasques¹,

Arnhold

Jorge³

2014

Horm Res Paediatr

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The C-type natriuretic peptide (CNP) and its receptor (NPR-B) are recognized as important regulators of longitudinal growth. Animal models involving CNP or NPR-B genes (Nppc or Npr2) support the fundamental role of CNP/NPR-B for endochondral ossification. Studies with these animals allow the development of potential drug therapies for dwarfism. Polymorphisms in two genes related to the CNP pathway have been implicated in height variability in healthy individuals. Biallelic loss-of-function mutations in NPR-B gene (NPR2) cause acromesomelic dysplasia type Maroteux, a skeletal dysplasia with extremely short stature. Heterozygous mutations in NPR2 are responsible for nonsyndromic familial short stature. Conversely, heterozygous gain-of-function mutations in NPR2 cause tall stature, with a variable phenotype. A phase 2 multicenter and multinational trial is being developed to evaluate a CNP analog treatment for achondroplasia. Pediatricians and endocrinologists must be aware of growth disorders related to natriuretic peptides, although there is still much to be learned about its diagnostic and therapeutic use.

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Section: Introductionmentioning

confidence: 93%

“…Over the past 2 years, three gain-of-function mutations of the NPR2 gene were described (table 3) [18,19,20]. The families with the p.V883M and p.A488P mutations showed a similar phenotype, mainly characterized by scoliosis, arachnodactyly and long hallux [18,20].…”

Section: Mutations In Natriuretic Peptide System and Tall Staturementioning

confidence: 99%

Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

Vasques¹,

Arnhold

Jorge³

2014

Horm Res Paediatr

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“…Mice or humans that overexpress CNP or activate natriuretic peptide receptor 2 (Npr2; guanylyl cyclase B) have a skeletal overgrowth phenotype ( Fig. 2; Yasoda et al 2004;Bocciardi et al 2007;Hannema et al 2013;Miura et al 2014), while mice that lack CNP (Nppc −/− ) or humans with heterozygous mutations in NPR2 exhibit skeletal dwarfism (Tsuji and Kunieda 2005;Nakao et al 2015).…”

Section: Therapeutic Strategies In Achondroplasiamentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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“…To date, 32 functional sequence variants, including 25 associated with AMDM, in the NPR2 gene have been reported (Bartels et al, 2004;Olney, 2006;Hachiya et al, 2007;Khan et al, 2012). Four other sequence variants in the gene resulted in nonsyndromic short stature (Vasques et al, 2013;Amano et al, 2014) and three in overgrowth syndromes (Miura et al, 2012;Hannema et al, 2013;Miura et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families

Ullah

Umair

Khan

et al. 2015

Annals of Human Genetics

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SummaryAcromesomelic dysplasia Maroteaux type (AMDM) is an autosomal recessive skeletal disorder characterized by disproportionate short stature with shortening of the acromesomelic sections of the limbs. AMDM is caused by mutations in the NPR2 gene located on chromosome 9p21-p12. The gene encodes the natriuretic peptide receptor B (NPR-B) that acts as an endogenous receptor for C-type natriuretic peptide (CNP). Both CNP and NPR-B are considered as important regulators of longitudinal growth. The study presented here investigated three consanguineous families (A, B, C) segregating AMDM in an autosomal recessive manner. Linkage in the families was established to the NPR2 gene on chromosome 9p12-21. Sequence analysis of the gene revealed two novel missense variants (p.Arg601Ser; p.Arg749Trp) in two families and a previously reported splice site variant (c.2986+2T>G) in the third family.

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An Activating Mutation in the Kinase Homology Domain of the Natriuretic Peptide Receptor-2 Causes Extremely Tall Stature Without Skeletal Deformities

Abstract: We report the first activating mutation within the kinase homology domain of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP.

Cited by 83 publications

References 42 publications

Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders

Fibroblast growth factor signaling in skeletal development and disease

Homozygous Sequence Variants in the NPR2 Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families

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