Identification of a germline CSPG4 variation in a family with neurofibromatosis type 1-like phenotype

Zhuanli Bai,Zhen Yang,Meiju Ji,Xinju Li,Lin Shi,Peng Hou,Yiping Qu

doi:10.1038/s41419-021-04056-1

Zhuanli Bai, Zhen Yang + Show 5 more

Open Access

https://doi.org/10.1038/s41419-021-04056-1

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Abstract

Neurofibromatosis type 1 (NF1), an autosomal dominant and multisystem disorder, is generally considered to be caused by NF1 inactivation. However, there are also numerous studies showing that Neurofibromatosis type 1-like phenotype can be caused by the abnormalities in the other genes. Through targeted parallel sequencing, whole-exome sequencing, de novo genomic sequencing, and RNA isoform sequencing, we identified a germline V2097M variation in CSPG4 gene probably increased susceptibility to a NF1-like phenotype family. Besides, a series of in vitro functional studies revealed that this variant promoted cell proliferation by activating the MAPK/ERK signaling pathway via hindering ectodomain cleavage of CSPG4. Our data demonstrate that a germline variation in the CSPG4 gene might be a high risk to cause NF1-like phenotype. To our knowledge, this is the first report of mutations in the CSPG4 gene in human diseases.

Highlights

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder first described in 1882, and is characterized by cafe-au-lait spots, freckling, and cutaneous neurofibromas, as well as iris hamartomas (Lisch nodules) and bone abnormalities [1, 2]
It is clear that NF1 is caused by inactivating mutations in the NF1 gene encoding the tumor suppressor protein neurofibromin [3, 4]
In addition to the NF1 gene, mutations in genes encoding some components participated in the RAS-mitogen-activated protein kinase (MAPK) pathway have been identified in human disorders, showing some phenotypic overlap with NF1, including PTPN11, KRAS (KRAS proto-oncogene, GTPase), SOS1 (SOS Ras/Rac guanine nucleotide exchange factor 1), RAF1 (Raf-1 proto-oncogene, serine/threonine kinase), RIT1 (Ras-like without CAAX 1), HRAS (HRas proto-oncogene, GTPase), BRAF (B-Raf proto-oncogene, serine/threonine kinase), and MEK1/ 2 (MAPK kinase 1/2) [8,9,10,11,12,13,14,15,16]

Summary

Introduction

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder first described in 1882, and is characterized by cafe-au-lait spots, freckling, and cutaneous neurofibromas, as well as iris hamartomas (Lisch nodules) and bone abnormalities [1, 2]. Neurofibromin is a negative regulator of RAS guanosine triphosphate activity and promotes the conversion of RAS into its inactivation form under normal conditions, thereby inhibiting cell growth [5]. This process is left unhindered, leading to uncontrolled cell proliferation when there are inactivating mutations in the NF1 gene. It should be noted that germline loss-of-function mutations in SPRED1

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