Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy
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ORIGINAL INVESTIGATION
Biallelic loss‑of‑function variants in NEMF cause central nervous system impairment and axonal polyneuropathy Ashfaque Ahmed1 · Meng Wang1 · Gaber Bergant2 · Reza Maroofian3 · Rongjuan Zhao1 · Majid Alfadhel4,5,6 · Marwan Nashabat4,6 · Muhammad Talal AlRifai4,5 · Wafaa Eyaid6,7,8 · Abdulrahman Alswaid9 · Christian Beetz10 · Yan Qin11 · Tengfei Zhu1 · Qi Tian1 · Lu Xia1 · Huidan Wu1 · Lu Shen1 · Shanshan Dong1 · Xinyi Yang1 · Cenying Liu1 · Linya Ma1 · Qiumeng Zhang1 · Rizwan Khan1 · Abid Ali Shah1 · Jifeng Guo11,12 · Beisha Tang11,12 · Lea Leonardis13,14 · Karin Writzl3 · Borut Peterlin3 · Hui Guo1,16 · Sajid Malik15 · Kun Xia1,17,18 · Zhengmao Hu1,16 Received: 15 July 2020 / Accepted: 28 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 phenotypecausative 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. Abbreviations AR Autosomal recessive RoH Regions of homozygosity LOD Log of the odds shRNA Short hairpin RNA ID Intellectual disability KD Knockdown Ashfaque Ahmed and Meng Wang have contributed equally to this work. * Gaber Bergant [email protected] * Sajid Malik [email protected] * Kun Xia [email protected] * Zhengmao Hu [email protected] Extended author information available on the last page of the article
ES Exome sequencing IF Immunofluorescence PBS Phosphate-buffered saline DD Developmental delay RQC Ribosome-associated quality control
Introduction Polyneuropathies are an informal group of neurological disorders with various etiologies, reaching a prevalence of 5–8% in the population, depending on a
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