ICA Plenary Lecture - Genetic Disorders of Human Spermatogenesis

by P.H. Vogt, Germany

Genetic disorders in human spermatogenesis have been commonly estimated at about 30%. They are associated phenotypically, mostly with azoospermia and severe idiopathic oligozoospermia. The causative gene mutations are presently unrepairable. Intracytoplasmic injection of spermatozoa (ICSI) and other haploid testicular gametes, although valuable in the treatment of severe male infertility, may transmit to ICSI offspring the following hazards: (1) sterility (monogenetic mutation risk); (2) habitual abortion (chromosomal aneuploidies); (3) gonadal defects; (4) dominant gene mutations (haploinsufficiency) in 50%; (5) polygenic inheritance of some diseases; (6) somatic gene defects (function haplosufficient) of high frequency in the population, despite its recessive nature; e.g. CFTR genes.

Such genetic disorders transmitted to ICSI offsprings necessitate that ICSI couples should be subjected to routine genetic counselling to explain the genetic risks of ICSI. Furthermore, attendant andrologists should be aware of the sex chromosome and autosome aneuploidies, and mutations in male gonad and somatic genes, which may lead to spermatogenic disruptions in the following manner:

1. Sex Chromosome Aneuploidies

(a) X chromosome polyploidy : as in 47, XXY (Klinefelter1s syndrome) where extra X chromosomes predispose to azoo and female phenotype development (micropenis, cryptorchidism, etc.), mental retardation, disproportionate growth of the legs, and other somatic anomalies, with estimated incidence of 1:500 in newborns. Klinefelter patients may occasionally demonstrate motile sperms in the ejaculate which is speculated to be due to a mosaic 46, XY cell line.

(b) Y chromosome polyploidy: estimated incidence is 1:750 newborns, may be fertile with frequent miscarriage of their wives, perinatal death and chromosomal anomalies of their children.

(c) Azoospermia with 46, XX karyotype: is rather rare (1:20000 newborns) showing variable degrees of intersexual phenotype depending on the degree of proximity to the sex-determining gene (SRY) locus on the distal Y short arm (Y p 11) and translocation to the distal X short arm (X p 22).

(d) Azoospermia with 45,X and mosaic 45,X/46,XY with streak gonad or normal external genitals due to a balanced Y-A-translocations.

(e) Azoospermia with deletion of the AZF a, b, c (azoospermia factor, or Yq11 deletions) and SCO syndromes of type I (germinal aplasia, or premeiotic spermatocyte arrest) and SCO type II (meiotic and spermatid arrest, and mixed SCO).

2. Autosomal Aneuploidies

(a) Numerical autosomal aneuploidies: fertile and infertile Down1s syndrome (trisomy 21) due to distortion of the sex vesicle.

(b) Structural autosomal aberrations: translocations and inversions are 10 times more frequent in infertile males, especially the pericentric inversions in chromosomes 1, 3, 5, 6, 10, and the Robertsonion translocations between 13 and 14 (acrocentric) interfering with meiosis.

3. Gene Mutations

(point mutations, small deletions and rearrangements): Our knowledge about genes functional in human spermatogenesis is still poor and mostly deduced from animal studies (Drosophila and rodents) through 3knockout2 technology, studying specific pathological phenotypes e.g. the CREM mouse HR 6B gene. Men with azoospermia and with OAT syndrome might now be analyzed for mutation in the clinic. Three human gene groups are supposed to be functional in spermatogenesis:

  1. Group 1: With specific expression pattern in the germ line such as AXFB and AZFC RBM, DAZ, and SPGY on the distal Yq 11, the SPGYLA (an ancestral homologous autosomal spermatogenesis gene for DA 2 and SPGY conserved in mouse1s Dazla and in Drosophila1s boule genes), the cyclin genes (cell-cycle regulators) expressed mostly at the premeiotic phase, the CREB (cAMP response element binding protein) and CREM (cAMP medulator) in germ cells and Sertoli cells.
  2. Group 2: With spermatogenic disruptions by mutations in male gonad, kidney, and gonadogenesis genes with a large variation of intersex, e.g. the SRY.
  3. Group 3: With spermatogenic disruptions by mutations in somatic genes as a pleiotropic effect with associated multiple genetic disorders such as the immotile cilia syndrome and CFTR gene (cystic fibrosis, bilateral aplasia vasa deferentia, pancreatic dysfunction). CFTR gene has high mutation rate in Caucasian populations (1:25, i.e. 4%), forms 1.5% of male sterility, with more than 350 mutations. A frequent CFTR mutation not inducing CF but CBAVD is the 5T allele in the 31splicing region of intron 8. Other clinical syndromes causing disruption of spermatogenesis are Noonan, Prader-Willi, Stein-Leventhal, and Fanconi's syndromes, etc.

Kamal Zaki Mahmoud, Egypt