Introduction: 46,XY gonadal dysgenesis is a condition that is characterised by undeveloped testes in individuals with a male karyotype. Mutations in many genes that underlie this condition have been identified; however, there are still a considerable number of patients with an unknown genetic background. Recently, a mutation in the STARD8 X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in Drosophila is responsible for maintaining testes integrity during their development. Methods: We analysed the potential pathogenicity of another STARD8 mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed. Results: These simulations revealed the full rearrangement of the helix containing the p.R887C substitution upstream from the START domain, which may cause STARD8 protein dysfunction and contribute to 46,XY gonadal dysgenesis. A comparison of the phenotypes of the three described 46,XY gonadal dysgenesis patients that harbour STARD8 mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype. Conclusion: Based on these and previous results, it is reasonable to include STARD8 in gene panels for 46,XY gonadal dysgenesis.

1.
Elzaiat
M
,
McElreavey
K
,
Bashamboo
A
.
Genetics of 46,XY gonadal dysgenesis
.
Best Pract Res Clin Endocrinol Metab
.
2022
;
36
(
1
):
101633
. doi: .
2.
Ilaslan
E
,
Calvel
P
,
Nowak
D
,
Szarras-Czapnik
M
,
Slowikowska-Hilczer
J
,
Spik
A
, et al
.
A case of two sisters suffering from 46,XY gonadal dysgenesis and carrying a mutation of a novel candidate sex-determining gene STARD8 on the X chromosome
.
Sex Dev
.
2018
;
12
(
4
):
191
5
. doi: .
3.
Kawai
K
,
Kiyota
M
,
Seike
J
,
Deki
Y
,
Yagisawa
H
.
START-GAP3/DLC3 is a GAP for RhoA and Cdc42 and is localized in focal adhesions regulating cell morphology
.
Biochem Biophys Res Commun
.
2007
;
364
(
4
):
783
9
. doi: .
4.
Holeiter
G
,
Bischoff
A
,
Braun
AC
,
Huck
B
,
Erlmann
P
,
Schmid
S
, et al
.
The RhoGAP protein Deleted in Liver Cancer 3 (DLC3) is essential for adherens junctions integrity
.
Oncogenesis
.
2012
;
1
(
6
):
e13
. doi: .
5.
Durkin
ME
,
Ullmannova
V
,
Guan
M
,
Popescu
NC
.
Deleted in Liver Cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth
.
Oncogene
.
2007
;
26
(
31
):
4580
9
. doi: .
6.
Sotillos
S
,
von der Decken
I
,
Domenech Mercadé
I
,
Srinivasan
S
,
Sirokha
D
,
Livshits
L
, et al
.
A conserved function of human DLC3 and Drosophila Cv-c in testis development
.
Elife
.
2022
;
11
:
e82343
. doi: .
7.
Karczewski
KJ
,
Francioli
LC
,
Tiao
G
,
Cummings
BB
,
Alföldi
J
,
Wang
Q
, et al
.
The mutational constraint spectrum quantified from variation in 141,456 humans
.
Nature
.
2020
;
581
(
7809
):
434
43
. doi: .
8.
1000 Genomes P
,
roject Consortium
,
Auton
A
,
Brooks
LD
,
Durbin
RM
,
Garrison
EP
,
Kang
HM
, et al
.
A global reference for human genetic variation
.
Nature
.
2015
;
526
(
7571
):
68
74
. doi: .
9.
Jumper
J
,
Evans
R
,
Pritzel
A
,
Green
T
,
Figurnov
M
,
Ronneberger
O
, et al
.
Highly accurate protein structure prediction with AlphaFold
.
Nature
.
2021
;
596
(
7873
):
583
9
. doi: .
10.
Bauer
P
,
Hess
B
,
Lindahl
E
, GROMACS. 2022.6 source code (2022.6). Zenodo.
2023
.
11.
Huang
J
,
MacKerell
AD
Jr
.
CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data
.
J Comput Chem
.
2013
;
34
(
25
):
2135
45
. doi: .
12.
Klein
F
,
Soñora
M
,
Helene Santos
L
,
Nazareno Frigini
E
,
Ballesteros-Casallas
A
,
Rodrigo Machado
M
, et al
.
The SIRAH force field: a suite for simulations of complex biological systems at the coarse-grained and multiscale levels
.
J Struct Biol
.
2023
;
215
(
3
):
107985
. doi: .
13.
Evans
DJ
,
Holian
BL
.
The Nose-Hoover thermostat
.
J Chem Phys
.
1985
;
83
(
8
):
4069
74
. doi: .
14.
Parrinello
M
,
Rahman
A
.
Polymorphic transitions in single crystals: a new molecular dynamics method
.
J Appl Phys
.
1981
;
52
(
12
):
7182
90
. doi: .
15.
Darden
T
,
York
D
,
Pedersen
L
.
Particle mesh Ewald: an N log(N) method for Ewald sums in large systems
.
J Chem Phys
.
1993
;
98
(
12
):
10089
92
. doi: .
16.
Brezovsky
J
,
Kozlikova
B
,
Damborsky
J
.
Computational analysis of protein tunnels and channels
.
Methods Mol Biol
.
2018
;
1685
:
25
42
. doi: .
17.
Gu
J
,
Liu
T
,
Guo
R
,
Zhang
L
,
Yang
M
.
The coupling mechanism of mammalian mitochondrial complex I
.
Nat Struct Mol Biol
.
2022
;
29
(
2
):
172
82
. doi: .
18.
Rayevsky
A
,
Sirokha
D
,
Samofalova
D
,
Lozhko
D
,
Gorodna
O
,
Prokopenko
I
, et al
.
Functional effects in silico prediction for androgen receptor ligand-binding domain novel I836S mutation
.
Life
.
2021
;
11
(
7
):
659
. doi: .
19.
Swigonska
S
,
Molcan
T
,
Nynca
A
,
Ciereszko
RE
.
The involvement of CYP1A2 in biodegradation of dioxins in pigs
.
PLoS One
.
2022
;
17
(
5
):
e0267162
. doi: .
20.
Arboleda
VA
,
Lee
H
,
Sánchez
FJ
,
Délot
EC
,
Sandberg
DE
,
Grody
WW
, et al
.
Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development
.
Clin Genet
.
2013
;
83
(
1
):
35
43
. doi: .
21.
Baxter
RM
,
Arboleda
VA
,
Lee
H
,
Barseghyan
H
,
Adam
MP
,
Fechner
PY
, et al
.
Exome sequencing for the diagnosis of 46,XY disorders of sex development
.
J Clin Endocrinol Metab
.
2015
;
100
(
2
):
E333
44
. doi: .
22.
Eggers
S
,
Sadedin
S
,
van den Bergen
JA
,
Robevska
G
,
Ohnesorg
T
,
Hewitt
J
, et al
.
Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort
.
Genome Biol
.
2016
;
17
(
1
):
243
. doi: .
23.
Hughes
IA
,
Houk
C
,
Ahmed
SF
,
Lee
PA
;
Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology Consensus Group
.
Consensus statement on management of intersex disorders
.
J Pediatr Urol
.
2006
;
2
(
3
):
148
62
. doi: .
24.
Knarston
I
,
Ayers
K
,
Sinclair
A
.
Molecular mechanisms associated with 46,XX disorders of sex development
.
Clin Sci
.
2016
;
130
(
6
):
421
32
. doi: .
25.
Ohnesorg
T
,
Vilain
E
,
Sinclair
AH
.
The genetics of disorders of sex development in humans
.
Sex Dev
.
2014
;
8
(
5
):
262
72
. doi: .
26.
Horenkamp
FA
,
Valverde
DP
,
Nunnari
J
,
Reinisch
KM
.
Molecular basis for sterol transport by StART-like lipid transfer domains
.
EMBO J
.
2018
;
37
(
6
):
e98002
. doi: .
You do not currently have access to this content.