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What is the precise mechanism of sex determination?
During early embryonic development, the two sexes are indistinguishable
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female fate was still unclear
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They are expressed specifically in
the testis and exist in multiple copies
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Reijo et al
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When it is
defective or absent, there are severe spermatogenic defects, ranging from the complete absence
of germ cells to spermatogenic arrest
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Graves remarks,
It is still quite unclear how (the action of) SRY precipitates testis differentiation, what other
genes SRY interacts with and even whether it is an activator or a repressor
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Our lack of precise information of the role of SRY is apparent in the XX male, who has
no SRY gene; some investigators have suggested that the actual role of SRY is to inhibit the
action of a gene yet to be identified whose role is actually to suppress the testis pathway
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They point out that until
the 7th 8th week of human development, the fetal gonad is composed of cells that make up the
“supporting cell lineage” which have the capacity to develop into Sertoli cells or follicle cells
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” These omnipotent cells provide an essential environmental
component for the proper action of SRY on the Y chromosome
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The Sry gene is the first of the Sox (Sry-related high-mobility group
box family of transcription factors that regulate gene expression)
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Conversely, female to male sex reversal in XX
subjects can occur when SRY is present due to X Y translocation
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Moreover, these investigators commented
that variations in SRY or NR5A1 (the gene involved in gonadal and adrenal differentiation)
genes only account for 10%
15% of cases each of 46,XY gonadal dysgenesis
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5% had a pathogenic finding,
12
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56 The patients
studied were classified by their external genitalia (20 of them had female external genitalia),
and a detailed description of the anatomy of their internal genitalia and gonads were provided
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The detailed discussion of their results demonstrates the importance of the interaction between
the sex chromosomes and genes on autologous chromosomes in ensuring the normal/successful
congruence between external and internal genitalia
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The turn-around time for exome sequencing in DSD patients is under
two weeks
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bring reassurance to patients and their families
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The diagnosis of AIS meant that she
would be unlikely to respond to T treatment
The finding of an NR5A1 variant previously reported in a male with isolated hypospadias was very
reassuring for this patient
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The next step in the development of the testis is due to the action of the Sox9 gene, a close
relative of the Sry, which is expressed in all Sertoli cells
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Deletion of this gene produces male-to-female sex reversal, while overexpression or
duplication results in female-to-male sex reversal
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describe an XX infant with sex
reversal due to the duplication of the Sox9 gene on chromosome 17; the child had abnormal male
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external genitalia (severe penile/scrotal hypospadias; gonads were palpable)
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This observation suggests that there are autosomal genes in the male sexual
differentiation pathway initiated by SRY and current data suggest that while the SRY is the switch
that begins the progression to maleness, it may act by regulating/promoting the Sox9 gene, which,
in itself, is the actual factor that produces testis formation
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1 For example, they point out that not only the Sry or Sox9 genes determine male
sex, but that extracellular signaling molecules may also be important in their expression
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The latter is
necessary to maintain Sox9 expression and with it testis differentiation
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This precarious balance of the gonad between these
two developmental pathways is likely what confers its dual potential
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Defects in these reinforcing signaling loops may explain many
disorders of incomplete sexual development that manifest as gonadal dysgenesis, ovotestis formation, ambiguous ductal or genitalia development or a combination of these
features

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