Molecular Genetic Pathogenesis
Gene structure
FAM111B comprises four exons. The ATG transcription start is located in exon 3.
Pathogenic variants
Almost all reported pathogenic variants in FAM111B are missense and clustered in a putative cysteine/serine trypsin-like peptidase domain of the FAM111B protein. Variants at amino acid residues p.Lys421, p.Gln430, p.Thr621, p.Thr625, p.Arg627, and p.Ser628 have been reported:
- The p.Thr621Asp pathogenic variant was reported in several affected members of a family with POIKTMP (Mercier, et al. 2015).
- The pathogenic variants p.Arg627Gly and p.Ser628Asn have been identified as de novo events in several unrelated affected individuals (Mercier, et al. 2013, Mercier, et al. 2015).
- Two pathogenic variants located in other regions of the gene, p.Gln430Pro and p.Lys421del, have been associated with a less severe phenotype (Mercier, et al. 2015, Seo, et al. 2016, Takeichi, et al. 2017).
Normal gene product
The FAM111B protein is predicted to contain a trypsin-like cysteine/serine peptidase domain. A role in DNA replication is suggested (Aviner, et al. 2015).
Abnormal gene product
The mechanism of disease for POIKTMP is hitherto unknown; however, the spectrum of pathogenic variants and functional studies suggest a dominant-negative mechanism (Mercier, et al. 2015, Unpublished data).