Detection of Folliculin Gene Mutations in Two Chinese Families with Birt-Hogg-Dube Syndrome

Lv Liu,Ting Guo,Xiaocui Xiao,Xiang Wang,Zhihui Shi,Kai Yang,Yifeng Yang,Hong Luo,Yu Yuan

doi:10.1155/2017/8751384

Abstract

Birt-Hogg-Dube syndrome (BHD, OMIM#135150) is a rare disease in clinic; it is characterized by skin fibrofolliculomas, pulmonary cysts with an increased risk of recurrent pneumothorax, renal cysts, and renal neoplasms. Previous studies have demonstrated that variants in folliculin (FLCN, NM_144997) are mainly responsible for this disease. In this research, we enrolled two BHD families and applied direct sequencing of FLCN to explore the genetic lesions in them. Two FLCN mutations were identified: one is a novel deletion variant (c.668delA/p.N223TfsX19), while the other is a previously reported insertion mutation (c.1579_1580insA/p.R527QfsX75). And the pathogenicity of both variants was confirmed by cosegregation assay. Bioinformatics analysis showed that c.668delA may lead to functional haploinsufficiency of FLCN because mRNA carrying this mutation exhibits a faster degradation rate comparing to the wild type. Real-time qPCR also confirmed that the mRNA level of FLCN expression in the proband was decreased significantly compared with the controls, which may disrupt the mTOR pathway and lead to BHD. The insertion mutation (c.1579_1580insA) was predicted to cause a prolonged amino acid sequence of FLCN. The present identification of two mutations not only further supports the important role of tumor suppressor FLCN in BHD and primary spontaneous pneumothorax, but also expands the spectrum of FLCN mutations and will provide insight into genetic diagnosis and counseling of families with BHD.

Highlights

Birt-Hogg-Dube syndrome (BHD, OMIM#135150) is a rare autosomal dominant disorder mainly featured by skin fibrofolliculomas, pulmonary cysts with an increased risk of recurrent pneumothorax, renal cysts, and renal neoplasms [1, 2]
In Family 2, proband 2, there was a 46-year-old male. He was admitted in the hospital due to primary spontaneous pneumothorax (PSP) and right renal neoplasms (Figures 2(a), 2(b), and 2(c))
The pathological section of his lung pathology presents pulmonary cyst (Figure 2(b)), while his renal tissue accords with renal cell carcinoma (Figure 2(e)). His mother suffered from PSP and renal neoplasms while his brother only presents PSP

Summary

Introduction

Birt-Hogg-Dube syndrome (BHD, OMIM#135150) is a rare autosomal dominant disorder mainly featured by skin fibrofolliculomas, pulmonary cysts with an increased risk of recurrent pneumothorax, renal cysts, and renal neoplasms [1, 2]. The renal neoplasms in BHD patients are predominantly presented hybrid oncocytic/chromophobe and subtype followed by the clear cell renal carcinomas [3]. There is no international consensus for surveillance of BHD patients. There is a rapid growing interest for clinical diagnosis of the FLCN mutations that underlie BHD since the discovery of the first variant in 2002 [8]. Approximately 169 variants of FLCN have been reported in BHD or isolated pneumothorax and renal carcinoma patients [2]. According to the data from LOVD database (https://grenada.lumc.nl/LOVD2/shared1/home.php?select db = FLCN), frameshift mutation and missense nutation are the common variants in BHD patients

Results

Discussion

Conclusion