title: Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports.
abstract: The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Jeju National University Hospital, Jeju, Republic of Korea.
authors.forename: Mi Hyun
authors.initials: MH
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Nawa
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Ohata
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Kitaoka
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Namba
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Dong Kyu
authors.initials: DK
authors.lastname: Jin
authors.affiliation: Department of Radiology, Woorisoa Children's Hospital, Seoul, Republic of Korea.
authors.forename: Ok Hwa
authors.initials: OH
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.affiliation: Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cho
mesh_terms: D000293:Adolescent; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000473:pathology*; D002648:Child; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B
keywords: C-type natriuretic peptide; NPR2; acromesomelic dysplasia, type Maroteaux; cGMP; short stature