2. Academic Validation
  3. Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy

Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy

  • Hum Genet. 2021 Apr;140(4):579-592. doi: 10.1007/s00439-020-02226-3.
Ashfaque Ahmed # 1,  Meng Wang # 1,  Gaber Bergant 2,  Reza Maroofian 3,  Rongjuan Zhao 1,  Majid Alfadhel 4 5 6,  Marwan Nashabat 4 6,  Muhammad Talal AlRifai 4 5,  Wafaa Eyaid 6 7 8,  Abdulrahman Alswaid 9,  Christian Beetz 10,  Yan Qin 11,  Tengfei Zhu 1,  Qi Tian 1,  Lu Xia 1,  Huidan Wu 1,  Lu Shen 1,  Shanshan Dong 1,  Xinyi Yang 1,  Cenying Liu 1,  Linya Ma 1,  Qiumeng Zhang 1,  Rizwan Khan 1,  Abid Ali Shah 1,  Jifeng Guo 11 12,  Beisha Tang 11 12,  Lea Leonardis 13 14,  Karin Writzl 3,  Borut Peterlin 3,  Hui Guo 1 15,  Sajid Malik 16,  Kun Xia 17 18 19,  Zhengmao Hu 20 21
Affiliations

Affiliations

  • 1 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • 2 Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia. [email protected].
  • 3 Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
  • 4 Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
  • 5 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
  • 6 Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
  • 7 King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia.
  • 8 Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre (KAIMRC), King Saud Bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
  • 9 Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 10 Centogene AG, Am Strande 7, 18057, Rostock, Germany.
  • 11 Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 12 National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, 410008, Hunan, China.
  • 13 Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
  • 14 Department of Neurology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
  • 15 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan, China.
  • 16 Human Genetics Program, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan. [email protected].
  • 17 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. [email protected].
  • 18 CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 19 Hunan Key Laboratory of Molecular Precisional Medicine, Central South University, Changsha, China. [email protected].
  • 20 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China. [email protected].
  • 21 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan, China. [email protected].
  • # Contributed equally.
PMID: 33048237 DOI: 10.1007/s00439-020-02226-3
Abstract

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.

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