Identification of a Novel NF1 Frameshift Variant in a Chinese Family with Neurofibromatosis Type 1

Author:

Xu Guoyao12,Li Ming3,Niu Youya1,Huang Xueshuang1,Li Yanchun2,Tang Genyun1,Long Sha4,Zhao Hui2,Jiang Haiou1ORCID

Affiliation:

1. Department of Cellular Biology and Genetics, Hunan Provincial Key Laboratory of Dong Medicine, Hunan University of Medicine, Huaihua, Hunan Province, China

2. Department of Neurology, The First Affiliated Hospital, Hunan University of Medicine, Huaihua, Hunan Province, China

3. Department of Histology and Embryology, Hunan University of Medicine, Huaihua, Hunan Province, China

4. Department of Oncology, The First Affiliated Hospital, Hunan University of Medicine, Huaihua, Hunan Province, China

Abstract

Neurofibromatosis type 1 (NF1) is a progressive neurocutaneous disorder in humans, mainly characterized by café-au-lait macules (CALMs) and neurofibromas. NF1 is caused by variants of the neurofibromin 1 gene (NF1), which encodes a Ras-GTPase-activating protein called neurofibromin. NF1 variants may result in loss of neurofibromin function and elevation of cell proliferation and tumor formation. In this study, a Chinese NF1 family with an autosomal dominant inheritance pattern was recruited. Exome sequencing and Sanger sequencing were performed to discover the causative variant responsible for the family, followed by molecular analysis of effect of the mutated NF1 protein on Ras activity. A novel frameshift variant c.541dupC (p.(Gln181Profs20)) in the NF1 gene was identified in all three affected family members. The variant cosegregated with the disease phenotypes in the pedigree and was absent in 100 healthy controls. Bioinformatic analysis showed that the variant c.541dupC (p.(Gln181Profs20)) was pathogenic. The further molecular analysis verified the cells expressing NF1 variant p.(Gln181Profs20) partially enhanced Ras activity and elevated cell proliferation and tumor formation due to loss of neurofibromin function caused by the variant. Taken together, the data strongly advocate the c.541dupC (p.(Gln181Profs20)) variant as the underlying genetic cause of the Chinese family with NF1. Moreover, our findings broaden the spectrum of NF1 variants and provide molecular insights into the pathogenesis of NF1.

Funder

Natural Science Foundation of Hunan Province

Publisher

Hindawi Limited

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine

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