Molecular genetics of rare puberty disorders in Finland and Denmark

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma


Sexual differentiation and pubertal development are complex processes whose disruption leads to the abnormal development of primary and/or secondary sexual characteristics. Although mutations in several genes have been implicated in these disorders, the majority of the patients still lack a molecular genetic diagnosis. The aim of this thesis work was to identify genetic defects underlying complete androgen insensitivity syndrome (CAIS), congenital hypogonadotropic hypogonadism (CHH) and gonadotropin-dependent precocious puberty (GDPP), in Finnish and Danish patients. The genetic cause of CAIS was investigated in two siblings without identified mutations in the androgen receptor gene (AR). Whole-genome sequencing and AR cDNA analysis revealed a deep intronic mutation that led to abnormal splicing of AR mRNA and undetectable amount of AR protein in patient fibroblasts. The genetic causes of both extremes of pubertal variation, GDPP and CHH, were investigated in Danish patients. Twenty-nine Danish girls with GDPP were screened for mutations in MKRN3, which was recently identified as a regulator of pubertal onset, and one girl was found to have a mutation in this gene. Forty-one Danish CHH patients were screened for mutations in the CHH genes ANOS1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. Additionally, CHD7 was screened in two patients with hearing loss. Twelve patients were found to have a conclusive mutation; either in FGFR1 (5), ANOS1 (4), GNRHR (1), or CHD7 (2). SEMA3A and SEMA7A, two candidate genes of CHH, were screened in fifty Finnish CHH patients. Three SEMA3A variants and two SEMA7A variants were identified in the patients, but the identified variants do not seem to be sufficient to cause CHH alone. In conclusion, the intronic AR mutation is the first reported case of pseudoexon activation leading to CAIS demonstrating the importance of AR cDNA analysis in AIS patients without a molecular genetic diagnosis. Mutations in MKRN3 underlie GDPP in Denmark, although they are not very common in sporadic cases. FGFR1, ANOS1, GNRHR, and CHD7 mutations were found to underlie CHH in the Danish patients, but the majority still remain without a molecular genetic diagnosis. Finally, mutations in SEMA3A and SEMA7A do not seem to contribute significantly to CHH, and it remains to be seen whether mutations in these genes cause CHH in humans.
Painoksen ISBN978-951-51-3532-2
Sähköinen ISBN978-951-51-3533-9
TilaJulkaistu - 2017
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)


  • Adolescent
  • Androgen-Insensitivity Syndrome
  • +genetics
  • Antigens, CD
  • DNA Mutational Analysis
  • Genetic Diseases, Inborn
  • Genetic Predisposition to Disease
  • Hypogonadism
  • Kallmann Syndrome
  • Mutation
  • Puberty
  • Puberty, Precocious
  • Receptors, Androgen
  • Receptors, LHRH
  • Ribonucleoproteins
  • Semaphorins
  • 3111 Biolääketieteet

Siteeraa tätä