PMID- 33048237
OWN - NLM
STAT- MEDLINE
DCOM- 20210330
LR  - 20240226
IS  - 1432-1203 (Electronic)
IS  - 0340-6717 (Linking)
VI  - 140
IP  - 4
DP  - 2021 Apr
TI  - Biallelic loss-of-function variants in NEMF cause central nervous system 
      impairment and axonal polyneuropathy.
PG  - 579-592
LID - 10.1007/s00439-020-02226-3 [doi]
AB  - 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.
FAU - Ahmed, Ashfaque
AU  - Ahmed A
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Wang, Meng
AU  - Wang M
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Bergant, Gaber
AU  - Bergant G
AD  - Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, 
      Ljubljana, Slovenia. kc39369@kclj.si.
FAU - Maroofian, Reza
AU  - Maroofian R
AD  - Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, 
      London, WC1N 3BG, UK.
FAU - Zhao, Rongjuan
AU  - Zhao R
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Alfadhel, Majid
AU  - Alfadhel M
AD  - Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, 
      Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
AD  - 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.
AD  - Medical Genomics Research Department, King Abdullah International Medical 
      Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), 
      Riyadh, Saudi Arabia.
FAU - Nashabat, Marwan
AU  - Nashabat M
AD  - Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, 
      Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
AD  - Medical Genomics Research Department, King Abdullah International Medical 
      Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), 
      Riyadh, Saudi Arabia.
FAU - AlRifai, Muhammad Talal
AU  - AlRifai MT
AD  - Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, 
      Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.
AD  - 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.
FAU - Eyaid, Wafaa
AU  - Eyaid W
AD  - Medical Genomics Research Department, King Abdullah International Medical 
      Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), 
      Riyadh, Saudi Arabia.
AD  - 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.
AD  - 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.
FAU - Alswaid, Abdulrahman
AU  - Alswaid A
AD  - Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
FAU - Beetz, Christian
AU  - Beetz C
AD  - Centogene AG, Am Strande 7, 18057, Rostock, Germany.
FAU - Qin, Yan
AU  - Qin Y
AD  - Department of Neurology, Xiangya Hospital, Central South University, Changsha, 
      410008, Hunan, China.
FAU - Zhu, Tengfei
AU  - Zhu T
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Tian, Qi
AU  - Tian Q
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Xia, Lu
AU  - Xia L
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Wu, Huidan
AU  - Wu H
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Shen, Lu
AU  - Shen L
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Dong, Shanshan
AU  - Dong S
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Yang, Xinyi
AU  - Yang X
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Liu, Cenying
AU  - Liu C
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Ma, Linya
AU  - Ma L
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Zhang, Qiumeng
AU  - Zhang Q
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Khan, Rizwan
AU  - Khan R
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Shah, Abid Ali
AU  - Shah AA
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
FAU - Guo, Jifeng
AU  - Guo J
AD  - Department of Neurology, Xiangya Hospital, Central South University, Changsha, 
      410008, Hunan, China.
AD  - National Clinical Research Center for Geriatric Disorders, Central South 
      University, Changsha, 410008, Hunan, China.
FAU - Tang, Beisha
AU  - Tang B
AD  - Department of Neurology, Xiangya Hospital, Central South University, Changsha, 
      410008, Hunan, China.
AD  - National Clinical Research Center for Geriatric Disorders, Central South 
      University, Changsha, 410008, Hunan, China.
FAU - Leonardis, Lea
AU  - Leonardis L
AD  - Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, 
      Ljubljana, Slovenia.
AD  - Department of Neurology, Faculty of Medicine, University of Ljubljana, Ljubljana, 
      Slovenia.
FAU - Writzl, Karin
AU  - Writzl K
AD  - Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, 
      London, WC1N 3BG, UK.
FAU - Peterlin, Borut
AU  - Peterlin B
AD  - Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, 
      London, WC1N 3BG, UK.
FAU - Guo, Hui
AU  - Guo H
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China.
AD  - Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan, China.
FAU - Malik, Sajid
AU  - Malik S
AD  - Human Genetics Program, Department of Animal Sciences, Faculty of Biological 
      Sciences, Quaid-i-Azam University, Islamabad, Pakistan. malik@qau.edu.pk.
FAU - Xia, Kun
AU  - Xia K
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China. 
      xiakun@sklmg.edu.cn.
AD  - CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), 
      Chinese Academy of Sciences, Shanghai, China. xiakun@sklmg.edu.cn.
AD  - Hunan Key Laboratory of Molecular Precisional Medicine, Central South University, 
      Changsha, China. xiakun@sklmg.edu.cn.
FAU - Hu, Zhengmao
AU  - Hu Z
AUID- ORCID: 0000-0002-3921-8205
AD  - Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School 
      of Life Sciences, Central South University, Changsha, Hunan, China. 
      huzhengmao@sklmg.edu.cn.
AD  - Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan, China. 
      huzhengmao@sklmg.edu.cn.
LA  - eng
GR  - 81730036/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20201013
PL  - Germany
TA  - Hum Genet
JT  - Human genetics
JID - 7613873
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (NEMF protein, human)
RN  - 0 (Nucleocytoplasmic Transport Proteins)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Alleles
MH  - Animals
MH  - Antigens, Neoplasm/*genetics
MH  - *Axons
MH  - Brain/metabolism
MH  - Cells, Cultured
MH  - Central Nervous System Diseases/*genetics
MH  - Consanguinity
MH  - Female
MH  - Gene Expression Profiling
MH  - Genes, Recessive
MH  - Homozygote
MH  - Humans
MH  - *Loss of Function Mutation
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Nucleocytoplasmic Transport Proteins/*genetics
MH  - Pedigree
MH  - Polyneuropathies/*genetics
MH  - RNA-Seq
MH  - Exome Sequencing
MH  - Young Adult
MH  - Mice
EDAT- 2020/10/14 06:00
MHDA- 2021/03/31 06:00
CRDT- 2020/10/13 12:13
PHST- 2020/07/15 00:00 [received]
PHST- 2020/09/28 00:00 [accepted]
PHST- 2020/10/14 06:00 [pubmed]
PHST- 2021/03/31 06:00 [medline]
PHST- 2020/10/13 12:13 [entrez]
AID - 10.1007/s00439-020-02226-3 [pii]
AID - 10.1007/s00439-020-02226-3 [doi]
PST - ppublish
SO  - Hum Genet. 2021 Apr;140(4):579-592. doi: 10.1007/s00439-020-02226-3. Epub 2020 
      Oct 13.