Further defining the clinical and molecular spectrum of acromesomelic dysplasia type maroteaux: a Turkish tertiary center experience

Şimşek‐Kiper, Pelin Özlem; Demir, Gizem Ürel; Taşkıran, Ekim Z.; Arslan, Ümüt; Nur, Banu; Mıhçı, Ercan; Haliloğlu, Mithat; Alanay, Yasemin; Ütine, Gülen Eda; Boduroğlu, Koray

doi:10.1038/s10038-020-00871-0

Cited by 7 publications

(6 citation statements)

References 39 publications

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“…Tricuspid regurgitation was found in patient 1 in our study and mitral valve insufficiency in a 54-year-old female patient and the above-mentioned boy with AMDM ( Simsek-Kiper et al, 2021 ). The co-occurrence of heart valve diseases may be because of the high parental consanguinity rate, which may contribute to heart valve diseases probably related to other gene mutations ( Simsek-Kiper et al, 2021 ). Although NPR-B has already been shown to mediate the effects of aortic valve development and disease in mice ( Blaser et al, 2018 ), the relationship between NPR2 and heart valve diseases is unclear and should be explored in the future.…”

Section: Discussionsupporting

confidence: 54%

“…WES analysis revealed the novel compound heterozygous mutations c.2887+2T>C and c.1112G>A p.(Arg371Gln) in NPR2 in patient 1. In addition, a homozygous missense mutation c.329G>A p.(Arg110His) was found in patient 2, which was recently reported ( Simsek-Kiper et al, 2021 ). The pathogenicity of the two novel mutations (c.2887+2T>C, c.1112G>A) was confirmed by segregation analysis, transcript analysis, and in silico analysis.…”

Section: Discussionsupporting

confidence: 51%

“…No radiological data were available for patient 2. Current information demonstrated that morphological changes in vertebral bodies with age may increase the risk for subsequent development of spinal stenosis ( Ain et al, 2019 ) and obstructive sleep apnea ( Huang et al, 2012 ; Simsek-Kiper et al, 2021 ), which will seriously influence patient quality of life and should be considered during follow-up. Tricuspid regurgitation was found in patient 1 in our study and mitral valve insufficiency in a 54-year-old female patient and the above-mentioned boy with AMDM ( Simsek-Kiper et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Current information demonstrated that morphological changes in vertebral bodies with age may increase the risk for subsequent development of spinal stenosis ( Ain et al, 2019 ) and obstructive sleep apnea ( Huang et al, 2012 ; Simsek-Kiper et al, 2021 ), which will seriously influence patient quality of life and should be considered during follow-up. Tricuspid regurgitation was found in patient 1 in our study and mitral valve insufficiency in a 54-year-old female patient and the above-mentioned boy with AMDM ( Simsek-Kiper et al, 2021 ). The co-occurrence of heart valve diseases may be because of the high parental consanguinity rate, which may contribute to heart valve diseases probably related to other gene mutations ( Simsek-Kiper et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…To date, 71 pathogenic mutations in NPR2 have been shown to be associated with AMDM based on an inclusive review of the literature ( Mustafa et al, 2020 ; Simsek-Kiper et al, 2021 ) (including the two current cases) and two databases (Human Gene Mutation Database and Leiden Open Variation Database; Supplementary Table S6 ; Supplementary Figure S7 ), including 39 missense mutations, 15 nonsense mutations, six splicing mutations, 10 deletions, and one insertion. Biallelic mutations in NPR2 that underlie AMDM are found throughout the entire length, except for in exons 9 and 18.…”

Section: Discussionmentioning

confidence: 99%

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Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type

Wang

Jiao

et al. 2022

Front. Genet.

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Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare skeletal dysplasia characterized by severe disproportionate short stature, short hands and feet, normal intelligence, and facial dysmorphism. Homozygous or compound heterozygous mutations in the natriuretic peptide receptor 2 (NPR2) gene produce growth-restricted phenotypes. The current study was designed to identify and characterize NPR2 loss-of-function mutations in patients with AMDM and to explore therapeutic responses to recombinant growth hormone (rhGH). NPR2 was sequenced in two Chinese patients with AMDM via next generation sequencing, and in silico structural analysis or transcript analysis of two novel variants was performed to examine putative protein changes. rhGH treatment was started for patient 1. Three NPR2 mutations were identified in two unrelated cases: two compound heterozygous mutations c.1112G>A p.(Arg371Gln) and c.2887+2T>C in patient 1 and a homozygous mutation c.329G>A p.(Arg110His) in patient 2, yielding distinct phenotypes. RNA extracted from peripheral blood cells of patient 1 showed alternatively spliced transcripts not present in control cells. Homology modeling analyses suggested that the c.1112G>A p.(Arg371Gln) mutation disrupted the binding of NPR-B homodimer to its ligand (C-type natriuretic peptide) in the extracellular domain as a result of global allosteric effects on homodimer formation. Thus, c.2887+2T>C and c.1112G>A p.(Arg371Gln) in NPR2 were loss-of-function mutations. Furthermore, rhGH therapy in patient 1 increased the patient’s height by 0.6SDS over 15 months without adversely affecting the trunk-leg proportion. The short-term growth-promoting effect was equivalent to that reported for idiopathic short stature. Overall, our findings broadened the genotypic spectrum of NPR2 mutations in individuals with AMDM and provided insights into the efficacy of rhGH in these patients.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type

Wang

Jiao

et al. 2022

Front. Genet.

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Resveratrol‐Induced Suppression of C‐type Natriuretic Peptide Associates With Increased Vertebral Bone Density in Postmenopausal Women

2023

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C‐type natriuretic peptide (CNP) is a paracrine growth factor essential in driving endochondral bone growth in mammals including humans. Despite evidence from animal experiments and tissues that CNP signaling stimulates osteoblast proliferation and osteoclast activity, whether CNP participates in bone remodeling in the mature skeleton is unknown. Using stored plasma samples from a previous randomized controlled clinical trial (RESHAW) of resveratrol supplementation in postmenopausal women exhibiting mild osteopenia, we have studied changes in plasma aminoterminal proCNP (NTproCNP) and concurrent change in bone turnover markers of formation (osteocalcin [OC] and alkaline phosphatase [ALP]) and resorption (C‐terminal telopeptide type 1 collagen [CTX]) with bone mineral density (BMD) over a 2‐year period of study in 125 subjects. In year one, subjects received placebo or resveratrol, switching to resveratrol or placebo, respectively, in year two. Across all time points, there were no significant associations of NTproCNP with CTX, ALP, or OC. During year one, plasma NTproCNP declined significantly in both groups. In the crossover comparison, analysis of change within individuals showed that, compared with placebo, NTproCNP declined after resveratrol (p = 0.011) and ALP increased (p = 0.008), whereas CTX and OC were unchanged. Inverse association of NTproCNP (r = −0.31; p = 0.025) and positive association of OC (r = 0.32, p = 0.022) with BMD at the lumbar spine were identified after resveratrol but not found after placebo. Decline in NTproCNP was independently associated with resveratrol treatment. This is the first evidence that CNP is modulated during a period of increasing BMD in postmenopausal women. Further study of NTproCNP and associations with drivers of bone formation or resorption can be expected to clarify CNP's role during other interventions directed to bone health in adults. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Acromesomelic Dysplasia I, Maroteaux Type (AMD1)

Naz

Mäkitie

2023

Genetic Syndromes

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Further defining the clinical and molecular spectrum of acromesomelic dysplasia type maroteaux: a Turkish tertiary center experience

Cited by 7 publications

References 39 publications

Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type

Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type

Resveratrol‐Induced Suppression of C‐type Natriuretic Peptide Associates With Increased Vertebral Bone Density in Postmenopausal Women

Acromesomelic Dysplasia I, Maroteaux Type (AMD1)

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