Foley A Reghan, Bolduc Véronique, Guirguis Fady, Donkervoort Sandra, Hu Ying, Orbach Rotem, McCarty Riley M, Sarathy Apurva, Norato Gina, Cummings Beryl B, Lek Monkol, Sarkozy Anna, Butterfield Russell J, Kirschner Janbernd, Nascimento Andrés, Natera-de Benito Daniel, Quijano-Roy Susana, Stojkovic Tanya, Merlini Luciano, Comi Giacomo, Ryan Monique, McDonald Denise, Munot Pinki, Yoon Grace, Leung Edward, Finanger Erika, Leach Meganne E, Collins James, Tian Cuixia, Mohassel Payam, Neuhaus Sarah B, Saade Dimah, Cocanougher Benjamin T, Chu Mary-Lynn, Scavina Mena, Grosmann Carla, Richardson Randal, Kossak Brian D, Gospe Sidney M, Bhise Vikram, Taurina Gita, Lace Baiba, Troncoso Monica, Shohat Mordechai, Shalata Adel, Chan Sophelia H S, Jokela Manu, Palmio Johanna, Haliloğlu Göknur, Jou Cristina, Gartioux Corine, Solomon-Degefa Herimela, Freiburg Carolin D, Schiavinato Alvise, Zhou Haiyan, Aguti Sara, Nevo Yoram, Nishino Ichizo, Jimenez-Mallebrera Cecilia, Lamandé Shireen R, Allamand Valérie, Gualandi Francesca, Ferlini Alessandra, MacArthur Daniel G, Wilton Steve D, Wagener Raimund, Bertini Enrico, Muntoni Francesco, Bönnemann Carsten G
Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
Dana-Dwek Children's Hospital, Tel Aviv 64239, Israel.
Brain. 2025 Apr 3. doi: 10.1093/brain/awaf116.
Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.
与胶原蛋白VI相关的肌营养不良症（COL6-RDs）表现出一系列临床表型，从乌尔里希先天性肌营养不良症（UCMD），其具有明显的先天性症状，特征为进行性肌无力、关节挛缩和呼吸功能不全，到贝斯勒姆肌营养不良症，其症状较轻，通常在后期才被识别，有时类似于肢带型肌营养不良症，以及介于UCMD和贝斯勒姆肌营养不良症之间的中间表型。尽管临床和肌肉病理学特征高度提示为COL6-RD，但一些患者在COL6A1、COL6A2或COL6A3中仍未发现致病变异。通过联合肌肉RNA测序和全基因组测序，我们在COL6A1的第11内含子中发现了一个反复出现的新生深度内含子变异（c.930+189C>T），该变异导致一个显性作用的框内假外显子插入。我们随后鉴定并描述了一个由44名具有这种COL6A1第11内含子致病变异的患者组成的国际队列，这是胶原蛋白6基因中最常见的反复出现的致病变异之一。患者表现出一致的严重表型，其特征是早期症状较少，随后加速进展为严重形式的UCMD，但有一名具有这种COL6A1第11内含子变异体细胞镶嵌现象的患者表现出与贝斯勒姆肌营养不良症一致的较轻表型。该个体疾病表型的部分改善为我们开发假外显子跳跃疗法以成功抑制假外显子插入提供了有力依据，从而产生正常的COL6A1转录本。我们之前已经表明，体外应用的剪接调节反义寡核苷酸有效地将含有突变假外显子的COL6A1转录本丰度降低到与此处所示体细胞镶嵌现象的体内情况相当的水平，表明这种治疗方法对于改善由这种常见反复出现的COL6A1变异引起的严重形式的UCMD具有重大的转化前景。
