A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency
A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency
复制标题
DOI：
10.1038/ejhg.2016.98
复制
发表时间：
2016-12-01
影响因子：
5.2
通讯作者：
Oldfors, Anders
中科院分区：
文献类型：
--
作者：
Hedberg-Oldfors, Carola;Darin, Niklas;Oldfors, Anders
我们描述了一种新的早发性神经肌肉疾病，由于后凸侧弯肽酶基因（KY）的纯合子功能丧失变异。一名7.5岁的女孩，从2岁起就有行走困难，表现为全身肌肉无力；肩膀、臀部和脚有轻微挛缩；和脚;前凸，但没有脊柱侧凸。她之前做过跟腱延伸手术。全身MRI显示小腿肌肉萎缩及脂肪浸润。股外侧肌的活检显示纤维大小的变化，有一些内化的核和许多非常小的纤维，发育中的肌球蛋白重链异构体的表达不同。部分小纤维可见异常肌瘤，z型椎间盘增厚，线状棒小。全外显子组测序显示，KY中存在纯合子单碱基缺失（c. 1071delG, p.(Thr358Leufs*3)），预计会导致一个截断的蛋白。RNA面板分析显示KY主要在人类骨骼肌中表达。小鼠同源基因Ky的一种隐性变异先前在一种自发产生的小鼠后凸性脊柱侧凸突变体中被描述过，这种突变体是由体位性肌肉营养不良引起的，是在出生后发生的。Xin和键结合伴侣丝蛋白C在我们患者肌纤维中的异常分布与它们在ky/ky小鼠肌纤维中的定位变化高度相似。我们描述了首例与KY失活相关的人类疾病病例。与小鼠模型一样，受影响的孩子表现出神经肌肉紊乱，但相比之下，没有脊柱后凸。
We describe a new early-onset neuromuscular disorder due to a homozygous loss-of-function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c. 1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder - but in contrast, no kyphoscoliosis.