Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.
Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome.
复制标题
扩大双糖链蛋白聚糖相关的 Meester-Loeys 综合征的临床范围。
DOI：
10.1038/s41525-024-00413-z
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发表时间：
2024
影响因子：
5.3
通讯作者：
Co
中科院分区：
文献类型：
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作者：
Meester,JosephinaAN;Hebert,Anne;Bastiaansen,Maaike;Rabaut,Laura;Bastianen,Jarl;Boeckx,Nele;Ashcroft,Kathryn;Atwal,PaldeepS;Benichou,Antoine;Billon,Clarisse;Blankensteijn,JanD;Brennan,Paul;Bucks,StephanieA;Campbell,IanM;Co
编码Biglycan的X连锁基因BGN的致病功能丧失变异与Meester-Loeys综合征(MRLS)有关，MRLS是一种胸主动脉瘤/夹层综合征。自2017年首次出版五个先证者以来，我们已大幅扩大最大似曾相识的队列，共有18个先证者(16名男性和2名女性)。分离分析确定了36名额外的携带BGNVariant的家庭成员(9名男性和27名女性)。通过对皮肤成纤维细胞的cDNA和Western Blot分析发现，已识别的BGN变异体会导致功能丧失，或者根据变异体的性质强烈预测会导致功能丧失。没有(可能)致病错义变异没有额外的(预测的)剪接效应被鉴定。有趣的是，一名男性先证者具有跨越BGN编码序列和下游基因5‘非翻译区(ATP2B3)的缺失，呈现出更严重的骨骼表型。这可能是因为下游的ATPaseATP2B3(通常在皮肤成纤维细胞中被抑制)在残留的BGN启动子的驱动下被表达激活。这项研究强调，MRLS中的动脉瘤和夹层延伸到胸主动脉以外，影响整个动脉树，心血管症状可能与非特异性结缔组织特征一致。此外，与女性相比，男性的临床表现更严重和更具穿透性。建议在确定已识别的BGN误义和非规范剪接变异体的致病性之前，在RNA、cDNA和/或蛋白质水平上进行广泛的分析，以证明功能丧失效应。总之，不同的机制可能是BGN中携带功能缺失变异的MRLS患者的广泛表型谱的基础。
Pathogenic loss-of-function variants inBGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additionalBGNvariant-harboring family members (9 males and 27 females). The identifiedBGNvariants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence ofBGNand the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPaseATP2B3(normally repressed in skin fibroblasts) driven by the remnantBGNpromotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identifiedBGNmissense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants inBGN.