Abstract
Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia. To date, only four variants have been reported; one nonsense, one splice-site, and two frameshifts in five AMDP families. Here, we report the first missense variant and a second splice-site variant in PRKG2 in two patients with clinical and radiological features of acromesomelic dysplasia. Furthermore, functional studies of the novel missense variant, p.Val470Gly, revealed that it was unable to down-regulate FGF2-induced MAPK signaling and, thus, would be predicted to cause growth delay. Hence, this report expands the mutational spectrum in skeletal dysplasias associated with PRKG2 variants. In addition, we propose recognizable facial features with acromesomelic dysplasia, PRKG2 type.
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Data availability
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We would like to express our sincere appreciation to Prof. Gen Nishimura for his support in the radiographic analysis of Patient 1. We would also thank patients and families who have participated in the study.
Funding
This work was partly supported by a grant (PID2020-116263RB-I00) from the Ministerio de Economia, Industria Competividad (to KEH). Francisca Díaz-González was a recipient of a FPU Ph.D. studentship from the Ministerio de Ciencia, Innovación y Universidades; Grant 303294/2020-5 (to AALJ) from the National Council for Scientific and Technological Development (CNPq); and by Coordination of Superior Level Staff Improvement (CAPES; Finance Code 001 to NLMA and LPC).
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OAD, FG-D YA, and KEH generated the outline of the manuscript, and OAD, FD-G, AALJ, YA, and KEH wrote the first draft. OAD, YA, AALJ, FD-G, and KEH prepared the tables and figures. OAD, FD-G, AALJ, NOM, NLMA, LPC, SC, MBTM, YA, and KEH revised the manuscript and approved the final version.
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AALJ received an independent research grant from BioMarin and consulting fees from Novo Nordisk. The other authors declare that they have no competing financial interests to declare.
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The Comite de Etica e Pesquisa do Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo (CAAE, 06425812.4.0000.0068) provided approval for this study. Written informed consent for genetics studies and publication of individual details and images was obtained.
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Akgun-Dogan, O., Díaz-González, F., de Lima Jorge, A.A. et al. Two new patients with acromesomelic dysplasia, PRKG2 type—identification and characterization of the first missense variant. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01472-z
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DOI: https://doi.org/10.1038/s41431-023-01472-z
