FLCN consists of 14 exons (Nickerson et al., 2002) spanning approximately 20 kb of genomic DNA. Nickerson et al. (2002) were the first to identify mutations in the FLCN gene. They screened nine BHD families and found that eight had truncating mutations (seven frameshift, one nonsense) in FLCN, five of which were in exon 11. Screening of an additional 53 BHD families found that 22 had mutations in exon 11, suggesting it is a mutation hotspot (Nickerson et al., 2002).
Schmidt et al. (2005) screened a further 30 families and after combining the mutational data, found that 53% of the FLCN mutations involved either a cytosine insertion or deletion in the mononucleotide tract of eight cytosines (C8) in exon 11. Further evidence supporting the theory of a mutation hotspot was provided by Khoo et al. (2002) when two FLCN germline mutations in exon 11 (c.1733insC and c.1733delC) were identified in three of four BHD families, as well as one of four sporadic cases of BHD syndrome. Nickerson and colleagues suggested that the frameshift mutations might be caused by a slippage-mediated mechanism during DNA replication (Nickerson et al., 2002). The majority of variants were predicted to introduce a premature stop codon into FLCN and therefore to result in protein truncation (Schmidt et al., 2005). It is unclear whether the truncated FLCN is targeted for degradation, or remains in the cell with altered or dominant negative function.
A number of large deletions in folliculin have been identified in families whom had been clinically diagnosed with BHD but had not been shown to have a mutation using DNA sequencing techniques (Benhammou et al., 2011, Ding et al., 2015). Benhammou et al., 2011 proposed a second mutation hotspot in the non-coding exon 1, which was found to contain the putative FLCN promoter, in their cohort but Ding et al., 2015 found a greater number of truncating mutations in their cohort.
There are two publicly available sequence variation databases for FLCN, which consolidate all identified FLCN mutations. Both are hosted online by the Leiden Open (source) Variation Database (LOVD), where researchers can submit published or unpublished mutations. The Folliculin Sequence Variation Database is curated by Dr Derek Lim (University of Birmingham, UK; Lim et al., 2010) and currently contains 152 FLCN mutations, as of January 2017. The second database is called http://www.skingenedatabase.com/ (Wei et al., 2009). Collating FLCN mutational data and combining this with clinical data is important as it allows the spectrum of mutations and genotype-phenotype correlations to be identified. This will help further the understanding of the causes of BHD syndrome and may lead to stratified management of BHD patients, should a genotype-phenotype correlation become evident.
Tables of FLCN mutations (updated 17th February 2016):
- Base Substitutions
- Base substitutions unlikely to be pathogenic
- FLCN variants not associated with BHD