FLCN consists of 14 coding exons (Nickerson et al., 2002) spanning approximately 20 kb of genomic DNA. The study by Nickerson et al. (2002) was the first to identify mutations in the FLCN gene. Of the nine BHD families screened, eight had frameshift or termination mutations within the 14 exons of FLCN. Five of these families had mutations in exon 11. Screening of an additional 53 BHD families found 22 had exon 11 mutations, suggesting 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. 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 mutations were predicted to introduce a premature stop codon into FLCN and therefore to result in protein truncation (Schmidt et al., 2005). This includes the ‘‘hot spot’’ mutations in exon 11. It is unclear whether the truncated FLCN is targeted for degradation, or remains in the cell with an altered function. 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 two of four sporadic cases of BHD syndrome.
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Both are hosted online by the Leiden Open (source) Variation Database (LOVD), where researchers can submit published or unpublished mutations.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 132 mutations which occur in all coding exons (4-14) of FLCN. The second database is called http://www.skingenedatabase.com/ (Wei et al., 2009). Combining FLCN mutational data is important as it allows trends to be easily identified, which can help further the understanding of the causes of BHD syndrome.
For a table detailing all FLCN mutations as described in the Folliculin Sequence Variation Database (up to Feb 2011), click the link below:
