BACKGROUND: Determination of
sex is the result of cascade of molecular events that cause undifferentiated bipotential
gonad to develop as a
testis or an
ovary . A series of
genes such as SRY, steroidogenic factor‑1 (SF1), AR, SRD5 α,
Desert hedgehog (DHH) etc., have been reported to have a significant
role in development of
sex in the
fetus and
secondary sexual characteristics at the
time of
puberty . Recently,
mitogen activated protein kinase kinase kinase 1 (MAP3K1)
gene was found to be associated with
46, XY disorders of sex development (DSD).
AIM: The present study is focused to identify
mutations in MAP3K1
gene in the cohort of 10 Indian
patients with
46,XY DSD including one
family with two affected
sisters . These
patients were already screened for SRY, SF1 and DHH
gene , but no
mutation was observed in any of these
genes . MATERIALS AND
METHODS: The entire
coding regions of MAP3K1 were amplified and sequenced using the
gene specific primers. RESULTS AND DISCUSSIONS
Sequence analysis of MAP3K1
gene has revealed four variants including one missense, two silent and one
deletion mutation . The
missense mutation p.D806N was observed in four
patients with
hypospadias . Two
patients showed the presence of
silent mutation p.Q1028Q present in
exon 14. Another
silent mutation p.T428T was observed in a
patient with
gonadal dysgenesis . We have also observed one
deletion mutation p. 942insT present in two
patients . The
pathogenicity of the
missense mutation p.D806N was carried out using in‑silico approach.
Sequence homology analysis has revealed that the
aspartate at 806 was found to be well‑conserved across species, indicated the importance of this residue. The score for polyphen
analysis of this
mutation was found to be 0.999 indicating to be pathogenic
mutation . Since, p.D806N
mutation was found to be important residue; it might contribute to
sexual development . We have reported the presence of
mutations /polymorphism in MAP3K1
gene . All the
mutations were found to be polymorphism upon comparing to
single nucleotide polymorphism database. However, in‑silico
analysis of the
missense mutation revealed to be a pathogenic
mutation .