FANCL has 2 described isoforms produced by alternative splicing. Isoform one (Q9NW38-1). Is known as the canonical isoform, while isoform 2 (Q9NW38-2) differs from the canonical sequence at 178-178: T--> TPQVNS.

The FANCL gene encodes FANCL protein comprised of 375 amino acids with a molecular mass of 42905 Da. FANCL is comprised of 3 domains, an N-terminal E2-like fold (ELF), a novel double-RWD (DRWD) and C-terminal RING domain (Hodson, Purkiss et al., 2014).

From total RNA sequencing, FANCL was found to be expressed in adrenal gland (RPKM 2.1), prostate (RPKM 2.34), thymus (RPKM 2.1), and thyroid (RPKM 2.2) (Bioproject PRJNA280600 (PMID 25970244 ). In another RNA sequencing project on 27 different tissues from 95 human individuals, FANCL was highly expressed in adrenal gland (RPKM 16.8), endometrium (RPKM 10.6), lymph nodes (RPKM 8.5), ovary (RPKM 9.2), prostate (RPKM 8.5), and testis (RPKM 12) (Bioproject PRJEB4337, PMID 24309898).

FANCL the catalytically active part of the 9 protein Fanconi anemia (FA) core complex comprised of FANCB, FAAP100, FANCA, FANCG, FAAP20, FANCC, FANCE and FANCF that forms in response to DNA damage incurred during DNA replication in S-phase, or to detection of interstand cross links (ICL) (Ceccaldi, Sarangi et al., 2016). FANCL is an E3 ubiquitin ligase that specifically monoubiquitinates FANCD2 (at lysine 561) and FANCI (at lysine 523) (ID2; Note the FANCD2-FANCI heterodimer "ID2" must not to be confused with the gene ID2) in the presence ofUBE2T (FANCT) to signal downstream DNA repair proteins. FANCL is comprised of 3 distinct functional domains: the RING domain interacts with the E2 conjugating enzyme UBE2T (FANCT), the central DRWD domain interacts with FANCD2, and the N-terminal E2-like fold domain (ELF) domain interacts with ubiquitin (Hodson et al., 2014, Miles, Frost et al., 2015). Within the core complex, FANCL interacts as a subcomplex with FANCB and FAAP100 (Huang, Leung et al., 2014, van Twest, Murphy et al., 2017); both proteins stabilize FANCL (Rajendra, Oestergaard et al., 2014), and enhance its activity 5-fold in vitro assays (Ling, Ishiai et al., 2007).
Along with FANCA, FANCG, FANCF, FANCL was found to interact directly with hairy enhancer of split 1 ( HES1), which is a part of the NOTCH1 developmental pathway involved hematopoietic stem cell (HSC) self-renewal (Tremblay, Huang et al., 2008). Depletion of HES1 from cells resulted in FA-like phenotype with disrupted interaction between individual core complex proteins, increased cell sensitivity to DNA crosslinking agents, and reduced MMC-induced ID2 monoubiquitination (Tremblay et al., 2008). Finally HES1 did not interact FA-mutated core complex proteins. HSC defects and eventual bone marrow failure in FA patients may be linked to inability of HES1 to interact with a defective core complex (Tremblay et al., 2008, Tremblay, Huang et al., 2018).

FANCL-associated Fanconi anemia is inherited in an autosomal recessive manner, and accounts for 0.2% of all FA cases (Wu, Liu et al., 2017). To date, there are only 9 documented cases of FANCL-associated FA (Ali, Kirby et al., 2009, Ameziane, Sie et al., 2012, Chandrasekharappa, Lach et al., 2013, Meetei, de Winter et al., 2003, Vetro, Iascone et al., 2015, Wu et al., 2017).
Of the 5 cases with phenotypic and genotypic data, four were severe, and one was mild. Two severe cases frame shift deletions in exon 4 and 6 that truncated FANC, resulted in postnatal mortality and presented with VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal malformations, and limb defects) (Vetro et al., 2015). Another case with homozygous frameshift insertion of exon 9 had a severe phenotype with esophageal atresia (Ameziane et al., 2012). Finally, a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) had a typical FA presentation with progression to bone marrow failture and death at age 9 from acute myelomonocytic leukemia (AML-M4) (Wu et al., 2017). The patient with mild FANCL-associated FA had bi-allelic mutation (Ali et al., 2009). One allele had an in-frame 3-bp deletion c.1007_1009delTAT (p.Ile336_Cys337delinsSer) in exon 12 within the PHD/RING-finger domain that resulted in loss of one amino acid, isoleucine-336, and conversion of cysteine-337 to serine null mutation (produces non-function protein). The other mutated allele had a 4-bp duplication (c.1095_1098dupAATT (p.Thr367AsnfsX13) that resulted in a frameshift just outside the RING-finger domain in exon 14. 4-bp duplication mutation is a hypomorphic mutation (produces partially functional protein) (Ali et al., 2009).
Sequencing screen of 27 FA cases with unidentified mutations uncovered 3 FANCL FA associated mutations: c.375-2033C>G (skips exons 4,6,7), c.375-2033 C>G (multiple splicing aberrations), c.1092G>A (skips exon 13), but didnt have corresponding phenotypic data (Chandrasekharappa et al., 2013). There is no phenotypic data for the first FANCL-associated FA patient that had exon 11 deletion and insertion of 177-nt sequence (Meetei et al., 2003) .