Table 1 Comparison of in vitro and in silico predicted activities of aminoacidic variants in CYP21A2 presumed to be involved in protein stability published since 2014.

Mutation	In vitro activity ± SD		In silico activity		Patient’s second mutation (REA%)	Patient’s phenotype	Reference
Mutation	17- OHP	P	Bovine model	Human crystal structure	Patient’s second mutation (REA%)	Patient’s phenotype	Reference
p.P45L	105 ± 10	ND	0.74	1.46	ND	SV	21
p.K102R	119.7 ± 25	ND	63.16	≥100	ND	NA	21
p.L122P	1.4 ± 2.1	−1.9 ± 5.2	0.11	0.25	Deletion (0)	SW	22
p.R149C	35.8 ± 14.6	47.3 ± 12.9	≥100	≥100	p.V281L (60)	NC	23
p.M150R	17.7 ± 1.9	4.6 ± 1.9	0.9	4.4	N	PB	22
p.A159T	126.6 ± 29.9	ND	≥100	≥100	N	AD	21
p.V211M	99.5 ± 32.4	ND	≥100	≥100	ND	SV/NC	21
p.A265S	90 ± 9	104 ± 15	≥100	≥100	N	NA	24
p.M283V	16.2 ± 9.3	19 ± 7	41.8	38.14	Deletion (0)	NC	23
p.M473I	85 ± 7	66 ± 12	≥100	64.12	p.V281L (60)	NC	24

In silico enzymatic activities were calculated from the fitting of the bovine based model and from the human crystal (Fig. 1) using the estimated ∆∆Gs of each of the mutants (Table S1). In vitro and in silico enzymatic activities are expressed in percentage relative to the wild type protein considered as 100%. In vitro enzymatic activities, patients’ second mutation and phenotypes are those reported in the bibliography. 17-OHP: 17-hydroxyprogesterone. P: Progesterone. REA: Residual enzymatic activity. ND: Not determined. N: Normal; NC. Nonclassical; SV: Simple virilizing; SW: Salt wasting; NA: Not Affected; PB: Premature Pubarche; AD: Addison Disease.

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