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 DARS1. 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. Dars1 knockout mice are embryonic lethal precluding examination of the etiology. To address this, we introduced the HBSL-causing Dars1^D367Y 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 Dars1^D367Y/D367Y mice with Dars1-null carriers. The resulting Dars1^D367Y/− offspring displayed a strong developmental delay compared to control Dars1^D367Y/+ littermates, starting during embryogenesis. Only a small fraction of Dars1^D367Y/− mice were born, and half of these mice died with hydrocephalus during the first 3 weeks of life. Of the few Dars1^D367Y/− mice that were born at term, 25% displayed microphthalmia. Throughout postnatal life, Dars1^D367Y/− mice remained smaller and lighter than their Dars1^D367Y/+ littermates. Despite this early developmental deficit, once they made it through early adolescence Dars1^D367Y/− 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 Dars1^D367Y/− mice compared to controls. Taken together, Dars1^D367Y/− 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 Dars1 knockout mice, and can be leveraged to test potential HBSL therapeutics including DARS1 gene replacement therapy.

脑干，脊髓受累和腿部痉挛（HBSL）引起的髓鞘过少是由天冬氨酰-tRNA合成酶编码基因的错义突变引起的白细胞营养不良 DARS1。临床表现包括获得性运动里程碑，痉挛，共济失调，癫痫发作，眼球震颤和智力障碍的消退。从形态上讲，HBSL的特征是中枢神经系统包括前脑干，小脑梗和上脑白质以及脊髓的背柱和外侧皮质脊髓束的低髓鞘形成。缺乏足够的HBSL动物模型。飞镖1敲除小鼠是致死性的胚胎致死性病原学检查。为了解决这个问题，我们引入了HBSL飞镖1^d367ÿ点突变进入小鼠基因组。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。由于亚型突变在反式缺失中更为严重，因此我们飞镖1^{d367ÿ/d367ÿ} 老鼠与 Dars1-null运营商。所结果的飞镖1^d367ÿ/-与对照相比，后代表现出强烈的发育延迟飞镖1^{d367ÿ/ +}同窝仔，从胚胎发生开始。只有一小部分飞镖1^d367ÿ/-小鼠出生，并且其中一半在生命的前三周死于脑积水。在少数飞镖1^{d367ÿ/ -}那是足月出生的小鼠，25％显示的小眼。在整个产后生活中，飞镖1^d367ÿ/-小鼠比它们的体积更小，更轻飞镖1^{d367ÿ/ +}同窝仔。尽管存在早期发育缺陷，但一旦青春期结束，飞镖1^{d367ÿ/ -}小鼠表型不起眼的大部分成年生活，直到他们开发的迟发性运动障碍以及空泡和脊髓白质脱髓鞘。主要髓鞘蛋白的表达水平降低。飞镖1^{d367ÿ/ -}小鼠与对照组相比。在一起飞镖1^d367ÿ/-小鼠对HBSL中相应的错义突变的临床图片进行建模。该模型将有助于研究迟发性缺陷，这在飞镖1 基因敲除小鼠，可用于测试潜在的HBSL治疗药物，包括 DARS1 基因替代疗法。