Abstract：
In the NAD biosynthetic network, the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme fuels NAD as a co-substrate for a group of enzymes. Mutations in the nuclear-specific isoform, NMNAT1, have been extensively reported as the cause of Leber congenital amaurosis-type 9 (LCA9). However, there are no reports of NMNAT1 mutations causing neurological disorders by disrupting the maintenance of physiological NAD homeostasis in other types of neurons. In this study, for the first time, the potential association between a NMNAT1 variant and hereditary spastic paraplegia (HSP) is described. Whole-exome sequencing was performed for two affected siblings diagnosed with HSP. Runs of homozygosity (ROH) were detected. The shared variants of the siblings located in the homozygosity blocks were selected. The candidate variant was amplified and Sanger sequenced in the proband and other family members. Homozygous variant c.769G>A:p.(Glu257Lys) in NMNAT1, the most common variant of NMNAT1 in LCA9 patients, located in the ROH of chromosome 1, was detected as a probable disease-causing variant. After detection of the variant in NMNAT1, as a LCA9-causative gene, ophthalmological and neurological re-evaluations were performed. No ophthalmological abnormality was detected and the clinical manifestations of these patients were completely consistent with pure HSP. No NMNAT1 variant had ever been previously reported in HSP patients. However, NMNAT1 variants have been reported in a syndromic form of LCA which is associated with ataxia. In conclusion, our patients expand the clinical spectrum of NMNAT1 variants and represent the first evidence of the probable correlation between NMNAT1 variants and HSP.
摘要：
在NAD生物合成网络中，烟酰胺单核苷酸腺苷酰转移酶(NMNAT)酶为NAD提供燃料作为一组酶的共底物。核特异性同工型的突变,NMNAT1已被广泛报道为Leber先天性黑蒙9型（LCA9）的原因。然而,尚无NMNAT1突变通过破坏其他类型神经元中生理NAD稳态的维持而导致神经系统疾病的报道。在这项研究中,第一次,描述了NMNAT1变体与遗传性痉挛性截瘫（HSP）之间的潜在关联。对诊断为HSP的两个受影响的兄弟姐妹进行全外显子组测序。检测纯合性(ROH)的运行。选择位于纯合性区块中的同胞的共有变体。在先证者和其他家族成员中扩增候选变体并对Sanger测序。纯合变体c.769G>A:p.（Glu257Lys）在NMNAT1中，是LCA9患者中NMNAT1的最常见变体，位于1号染色体的ROH中，被检测为可能的致病变体。在NMNAT1中检测到作为LCA9致病基因的变异后，我们进行了眼科和神经系统的再评估.未检测到眼科异常，这些患者的临床表现与纯HSP完全一致。以前从未在HSP患者中报道过NMNAT1变异。然而,已经报道了NMNAT1变体以与共济失调相关的LCA的综合征形式存在。总之,我们的患者扩大了NMNAT1变异的临床范围,是NMNAT1变异与HSP之间可能存在相关性的第一个证据.
