Fröhlich Dominik, Mendes Marisa I, Kueh Andrew J, Bongers Andre, Herold Marco J, Salomons Gajja S, Housley Gary D, Klugmann Matthias
Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, Kensington, NSW, Australia.
Metabolic Unit/Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Front Cell Neurosci. 2021 Jan 20;14:625879. doi: 10.3389/fncel.2020.625879. eCollection 2020.
Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL) is a leukodystrophy caused by missense mutations of the aspartyl-tRNA synthetase-encoding gene . The clinical picture includes the regression of acquired motor milestones, spasticity, ataxia, seizures, nystagmus, and intellectual disabilities. Morphologically, HBSL is characterized by a distinct pattern of hypomyelination in the central nervous system including the anterior brainstem, the cerebellar peduncles and the supratentorial white matter as well as the dorsal columns and the lateral corticospinal tracts of the spinal cord. Adequate HBSL animal models are lacking. knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing point mutation into the mouse genome. Surprisingly, mice carrying this mutation homozygously were phenotypically normal. As hypomorphic mutations are more severe in trans to a deletion, we crossed mice with carriers. The resulting offspring displayed a strong developmental delay compared to control littermates, starting during embryogenesis. Only a small fraction of mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, mice remained smaller and lighter than their littermates. Despite this early developmental deficit, once they made it through early adolescence mice were phenotypically inconspicuous for most of their adult life, until they developed late onset motor deficits as well as vacuolization and demyelination of the spinal cord white matter. Expression levels of the major myelin proteins were reduced in mice compared to controls. Taken together, mice model aspects of the clinical picture of the corresponding missense mutation in HBSL. This model will enable studies of late onset deficits, which is precluded in knockout mice, and can be leveraged to test potential HBSL therapeutics including gene replacement therapy.
伴有脑干和脊髓受累及腿部痉挛的髓鞘形成低下症（HBSL）是一种由天冬氨酰 - tRNA合成酶编码基因突变导致的脑白质营养不良。临床表现包括已获得的运动里程碑倒退、痉挛、共济失调、癫痫发作、眼球震颤和智力障碍。形态学上，HBSL的特征是中枢神经系统中独特的髓鞘形成低下模式，包括前脑干、小脑脚和幕上白质以及脊髓的后索和外侧皮质脊髓束。目前缺乏合适的HBSL动物模型。基因敲除小鼠胚胎致死，无法对病因进行研究。为了解决这个问题，我们将导致HBSL的点突变引入小鼠基因组。令人惊讶的是，纯合携带这种突变的小鼠在表型上是正常的。由于亚效突变在与缺失的反式作用中更严重，我们将基因敲除小鼠与携带突变的小鼠杂交。与对照同窝小鼠相比，产生的后代在胚胎发育期间就开始出现严重的发育延迟。只有一小部分杂交小鼠出生，其中一半在出生后的前3周内因脑积水死亡。在足月出生的少数杂交小鼠中，25%表现为小眼症。在整个出生后的生命过程中，杂交小鼠一直比它们同窝小鼠更小更轻。尽管有这种早期发育缺陷，但一旦它们度过青春期早期，杂交小鼠在成年后的大部分时间里在表型上并不明显，直到它们出现迟发性运动缺陷以及脊髓白质空泡化和脱髓鞘。与对照组相比，杂交小鼠中主要髓鞘蛋白的表达水平降低。综上所述，杂交小鼠模拟了HBSL中相应错义突变的临床表型。这个模型将能够研究迟发性缺陷，而这在基因敲除小鼠中是无法进行的，并且可以用于测试包括基因替代疗法在内的潜在HBSL治疗方法。
