Posts Tagged ‘ligand’

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Genetics and Male Endocrinology

Image Source: Created by Noam Steiner Tomer 8/10/2020

Male sexual differentiation and development proceed under direct control of androgens.  Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. Mutations in the androgen receptor gene cause phenotypic abnormalities of male sexual development that range from a:

  • female phenotype (complete testicular feminization), to that of
  • under-virilized or infertile men.

Using the tools of molecular biology, it was analyzed androgen receptor gene mutations in 31 unrelated subjects with androgen resistance syndromes. Most of the defects are due to nucleotide changes that cause premature termination codons or single amino acid substitutions within the open reading frame encoding the androgen receptor, and the majority of these substitutions are localized in three regions of the androgen receptor:

Less frequently, partial or complete gene deletions have been identified. Functional studies and immunoblot assays of the androgen receptors in patients with androgen resistance indicate that in most cases the phenotypic abnormalities are the result of impairment of receptor function or decreases in receptor abundance or both.

In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46, XY individuals.

The complete form of androgen insensitivity syndrome is characterized by

  • 46, XY karyotype,
  • external female phenotype,
  • intra-abdominal testes,
  • absence of uterus and ovaries,
  • blindly ending vagina, and
  • gynecomastia.

There is also a group of disorders of androgen action that result from partial impairment of androgen receptor function. Clinical indications can be abnormal sexual development of individuals with a

  • predominant male phenotype with
  • severe hypospadias and micropenis or of individuals with a
  • predominantly female phenotype with cliteromegaly,
  • ambiguous genitalia, and
  • gynecomastia.

Complete or gross deletions of the androgen receptor gene have not been frequently found in persons with the complete androgen insensitivity syndrome, whereas point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain have been reported in both partial and complete forms of androgen insensitivity, with a relatively high number of mutations in two clusters in exons 5 and 7.

The number of mutations in exon 1 is extremely low, and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain.

The X-linked condition of spinal and bulbar muscle atrophy (Kennedy’s disease) is characterized by a progressive motor neuron degeneration associated with signs of androgen insensitivity and infertility. The molecular cause of spinal and bulbar muscle atrophy is an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.

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