Molecular Characteristics
The FBXL4 (F-Box and Leucine-Rich Repeat Protein 4) gene is located at 6q16.1-q16.2 and encodes a 40-residue protein that binds SKP1 (modular E3 ubiquitin protein ligases) which is involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. FBXL4 plays a role in controlling bioenergetic homeostasis in cells and maintaining mitochondrial DNA.
Mutations and pathophysiology
The total number of pathogenic variants known to date is 47 and are summarized by El-Hattab et al. (2017). A few selected examples of allelic variants are described below:
Gai et al. (2013) reported nine FBXL4 (GenBank NM_012160.3) mutations in seven unrelated mitochondrial disease families, composed of three siblings and six singletons:
- 1703G>C (p.Gly568Ala) homozygous missense mutation
- 1444C>T (p.Arg482Trp) homozygous missense mutation in three individuals
- 1694A>G (p.Asp565Gly) homozygous missense mutation
- 1652T>A (p.Ile551Asn) homozygous missense mutation
- 1229C>T (p.Ser410Phe) homozygous missense mutation
- Two Compound heterozygous mutations, carrying nonsense mutations together with missense mutations, c.1790A>C; 1067del (p.Gln597Pro; Gly356fs) and c.614T>C; 106A>T, (p.Ile205Thr; Arg36Stop).
Early-onset encephalopathy, lactic acidosis, hypotonia, progressive brain atrophy, and global developmental delay were the most consistent reported clinical findings.
Bonnen et al. (2013) reported homozygosity for a c.1555C>T (p.Gln519∗) mutation in 5 individuals from a highly consanguineous family. The paper also identified homozygosity for a 1303C>T (p.Arg435∗) nonsense mutation in one individual and a c.1703G>C mutation, which affects the splicing of exon 9 of the gene, in another individual. The clinical features were similar to those reported by Gai et al. (2013), but less severe in the individual with the c.1703G>C mutation.