Mutation analysis of mitogen activated protein kinase 1 gene in Indian cases of 46,XY disorder of sex development.
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Date
2013-10
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Abstract
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.
Description
Keywords
Disorders of sex development, mitogen activated protein kinase kinase kinase 1, mutation
Citation
Das Dhanjit Kumar, Rahate Subodh G, Mehta Bhakti P, Gawde Harshavardhan M, Tamhankar Parag M. Mutation analysis of mitogen activated protein kinase 1 gene in Indian cases of 46,XY disorder of sex development. Indian Journal of Human Genetics. 2013 Oct-Dec ;19 (4): 437-442.