Table 1.

Overview of KLB gene variants and their phenotypic associations reported in the literature.

KLB variant	Functional assay	Cell line	Phenotype association	Study
Arg728Gln	↑ Protein stability	HEK293	Colonic transit at 24 hours	Wong et al., 2011 (19).
Arg728Gln	↓ Protein expression ↑ Lipid accumulation	HepG2 Huh7	Ballooning and lobular inflammation in pediatric NAFLD	Dongiovanni et al., 2020 (20).
Arg728Gln	↓ Protein expression ↑ Pro-fibrogenic genes induction ↑ Cell proliferation	LX-2	Lobular inflammation and hepatic fibrosis in MAFLD	Panera et al., 2021 (21).
Arg309Trp	↓ FGF21 signaling, ↓ Cell surface expression, ↓ Expression, ↓ Maturation level	L6 myoblasts	CHH	Xu et al., 2017 (22).
Arg309Gln	↓ FGF21 signaling ↓ Cell surface expression	L6 myoblasts	CHH	Xu et al., 2017 (22).
Arg424Cys	↓ FGF21 signaling ↓ Maturation level	L6 myoblasts	CHH	Xu et al., 2017 (22).
Ala574Thr	↓ Cell surface expression ↓ Maturation level	L6 myoblasts	CHH	Xu et al., 2017 (22).
Phe777delPhe	↓ FGF21 signaling ↓ Cell surface expression	L6 myoblasts	CHH	Xu et al., 2017 (22).
Lys815Glu	↓ FGF21 signaling ↓ Cell surface expression ↓ Maturation level	L6 myoblasts	CHH	Xu et al., 2017 (22).
Leu1011Pro	↓ FGF21 signaling ↓ Cell surface expression ↓ Maturation level	L6 myoblasts	CHH	Xu et al., 2017 (22).
Ser9Tyr (digenic with Val102Ile in FGFR1)	↓ FGF21 stimulated ERK phosphorylation	L6 myoblasts	Insulin-mediated pseudoacromegaly	Stone et al., 2020 (23).

CHH, congenital hypogonadotrophic hypogonadism; NAFLD, non-alcoholic fatty liver disease; MAFLD, metabolic-associated fatty liver disease; FGF21, fibroblast growth factor 21; ERK, extracellular signal-regulated kinases.