Yamada Hiroyuki, Nishida Yoshinobu, Maihara Toshiro, Sa'adah Nihayatus, Harahap Nur Imma Fatimah, Nurputra Dian Kesumapramudya, Ar Rochmah Mawaddah, Nishimura Noriyuki, Saito Toshio, Kubo Yuji, Saito Kayoko, Nishio Hisahide
Department of Pediatrics, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan; Department of Pediatrics, Toyooka Public Hospital, Toyooka, Hyogo, Japan.
Department of Pediatrics, Hyogo Prefectural Tsukaguchi Hospital, Amagasaki, Hyogo, Japan.
Pediatr Neurol. 2015 Jun;52(6):638-41. doi: 10.1016/j.pediatrneurol.2015.02.023. Epub 2015 Feb 28.
Spinal muscular atrophy is caused by survival motor neuron gene SMN1 mutations. SMN1 produces a full-length SMN1 protein isoform encoded by exons 1-7, and an axonal-SMN protein isoform encoded by exons 1-3 and intron 3. The axonal-SMN protein is expressed only in the embryonic period and plays a significant role in axonal growth. However, there has been no report on contribution of axonal-SMN to spinal muscular atrophy severity until now.
Two Japanese boys with spinal muscular atrophy type 1 in our study presented with generalized muscle weakness and respiratory insufficiency soon after birth and required an artificial ventilator from early infancy. Patient 1 was compound heterozygous for two SMN1 mutations, whole-gene deletion, and an intragenic mutation (c.819_820insT). He retained one copy of SMN1 producing the N-terminal part of SMN1 including axonal-SMN. On the other hand, patient 2 was homozygous for SMN1 deletion. Both of them showed the same copy number of spinal muscular atrophy-modifying genes, NAIP and SMN2. These findings suggested that the C-terminal domain of full-length SMN1 determined the severity, irrespective of presence or absence of axonal-SMN expression.
In patient 1, the C-terminal domain of full-length SMN1 determined spinal muscular atrophy severity, rather than the axonal-SMN, one copy of which could be present and intact. The presence or absence of axonal-SMN may not impact disease severity in spinal muscular atrophy type 1 patients.
脊髓性肌萎缩症由生存运动神经元基因SMN1突变引起。SMN1产生一种由外显子1 - 7编码的全长SMN1蛋白异构体，以及一种由外显子1 - 3和内含子3编码的轴突型SMN蛋白异构体。轴突型SMN蛋白仅在胚胎期表达，在轴突生长中起重要作用。然而，迄今为止，尚无关于轴突型SMN对脊髓性肌萎缩症严重程度影响的报道。
我们研究中的两名日本1型脊髓性肌萎缩症男孩出生后不久即出现全身肌无力和呼吸功能不全，婴儿早期就需要人工呼吸机。患者1为两个SMN1突变的复合杂合子，即全基因缺失和一个基因内突变（c.819_820insT）。他保留了一个产生包括轴突型SMN在内的SMN1 N端部分的SMN1拷贝。另一方面，患者2为SMN1缺失纯合子。他们两者的脊髓性肌萎缩症修饰基因NAIP和SMN2的拷贝数相同。这些发现表明，全长SMN1的C端结构域决定了严重程度，而与轴突型SMN的表达与否无关。
在患者1中，全长SMN1的C端结构域决定了脊髓性肌萎缩症的严重程度，而非轴突型SMN，轴突型SMN的一个拷贝可能存在且完整。轴突型SMN的有无可能不会影响1型脊髓性肌萎缩症患者的疾病严重程度。
