Yanchun Yuan1, Zhen Liu1, Xuan Hou1, Wanzhen Li2, Jie Ni1, Ling Huang1, Yiting Hu1, Pan Liu1, Xiaorong Hou1, Jin Xue1, Qiying Sun1, Yun Tian1, Bin Jiao1, Ranhui Duan1, Hong Jiang1, Lu Shen1, Beisha Tang1, Junling Wang2. 1. From the Department of Neurology (Y.Y., Z.L., X.H., W.L., J.N., Y.H., P.L., X.H., Q.S., Y.T., B.J., H.J., L.S, B.T., J.W.) and National Clinical Research Center for Geriatric Diseases (H.J., L.S, B.T., J.W.), Xiangya Hospital, Department of Neurology (L.H.), the Third Xiangya Hospital, Laboratory of Medical Genetics (J.X., R.D., H.J., L.S, B.T., J.W.), and Key Laboratory of Hunan Province in Neurodegenerative Disorders (J.H., L.S, B.T., J.W.), Central South University, Changsha, Hunan, PR China. 2. From the Department of Neurology (Y.Y., Z.L., X.H., W.L., J.N., Y.H., P.L., X.H., Q.S., Y.T., B.J., H.J., L.S, B.T., J.W.) and National Clinical Research Center for Geriatric Diseases (H.J., L.S, B.T., J.W.), Xiangya Hospital, Department of Neurology (L.H.), the Third Xiangya Hospital, Laboratory of Medical Genetics (J.X., R.D., H.J., L.S, B.T., J.W.), and Key Laboratory of Hunan Province in Neurodegenerative Disorders (J.H., L.S, B.T., J.W.), Central South University, Changsha, Hunan, PR China. junling.wang@csu.edu.cn.
Abstract
OBJECTIVE: To determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS). METHODS: In this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2) and polynucleotide repeat expansions in NOP56 and AR genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients. RESULTS: GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, p = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness-dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration. CONCLUSION: Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.
OBJECTIVE: To determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS). METHODS: In this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2) and polynucleotide repeat expansions in NOP56 and AR genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients. RESULTS:GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, p = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness-dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration. CONCLUSION: Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.