Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia
Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia
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DOI：
10.1136/jmedgenet-2020-107177
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发表时间：
2022-01-01
影响因子：
4
通讯作者：
Heath, Karen E.
中科院分区：
文献类型：
--
作者：
Diaz-Gonzalez, Francisca;Wadhwa, Saruchi;Heath, Karen E.
背景C型利钠肽（CNP）、其内源性受体利钠肽受体B（NPR-B）及其下游介导物环磷酸鸟苷（cGMP）依赖性蛋白激酶II（cGKII）在软骨形成分化和软骨内骨生长中发挥关键作用。在人类中，编码NPR-B的NPR 2的双等位基因变体导致Maroteaux型肢端中肢发育不良，而编码CNP的NPR 2（利钠肽受体2）和NPPC（利钠肽前体C）的杂合变体导致较轻的表型。相比之下，迄今为止，在人类中没有报道由蛋白激酶cGMP依赖性II型基因（PRKG 2）编码的cGKII变体，尽管其在纵向生长中的作用已在几种动物模型中得到明确证明。方法对2例因肢端中肢短缩、短指、轻中度扁平脊椎和长骨干骺端进行性增加改变而导致的严重矮小女孩进行外显子组测序。对鉴定的变体进行功能表征。结果发现两种纯合的PRKG 2突变体，一种为无义突变体，一种为移码突变体。突变体转录物暴露于无义介导的衰变，并且部分或完全缺乏激酶结构域的截短的突变体cGKII蛋白通过不能使c-Raf 1在Ser 43处磷酸化而改变下游促分裂原活化蛋白激酶信号传导途径，并且随后降低响应成纤维细胞生长因子2的ERK 1/2活化。它们还通过SOX 9下调COL 10A 1并上调COL 2A 1表达。结论：我们发现了一种新的肢端中肢发育不良，PRKG 2型（AMDP）。
Background C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models. Methods Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants. Results Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9. Conclusion In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).