Biology Reference
In-Depth Information
The uniform pathologic phenotype, its origin as a consequence of a systematic
alteration during spermiogenesis, the fact that seminal characteristics remain
constant along clinical evolution and even after pharmacologic induction of germ
cell depletion-repopulation and the familial incidence reported in men and bulls
(Bloom and Birch
1970
; Baccetti et al.
1989
, Chemes et al.
1999
) indicate that this
distinctive phenotype is a centrosome-related primary sperm defect that results
from an abnormal spermatogenic programming of genetic origin. Very recently,
Liska et al. (
2009
) and Kierszenbaum et al. (
2011
) reported mutations in Centrobin
and IFT88, two sperm proteins that localize to spermatid centrioles and manch-
ettes. Both phenotypes show separation of centrioles from their normal nuclear
attachment site, disruption of head-tail coupling, and spermatid decapitation. No
communication of similar mutations in humans is available to date.
All reported patients suffered from long standing primary sterility. In some cases
acephalic forms predominate, which makes impossible any attempt at assisted
reproduction (LeLannou
1979
; Perotti et al.
1981
; Holstein et al.
1986
; Chemes et al.
1987b
,
1999
; Baccetti et al.
1989
;Toyamaetal.
2000
). However, in other patients there
were good numbers of nucleated forms with alterations in the head-midpiece align-
ment. This opened the way to consider their use in oocyte microinjections. In the first
reported attempt, nucleated spermatozoa were microinjected into four good quality
metaphase II oocytes (Chemes et al.
1999
). All of them fertilized and formed pronuclei,
but zygotes remained at the pronuclear stage and degenerated before syngamy and
cleavage (Fig.
2.5
). Comparable results were communicated by Saias Magnan et al.
(
1999
) and Rawe et al. (
2002
), but this last report also documented high bhCG plasma
levels followed by preclinical abortions when microinjected spermatozoa were
rigorously selected avoiding anomalies of the head-neck junction. When these
abnormal spermatozoa were used in a heterologous bovine-human ICSI system, sperm
asters either failed to form or had an arrested development (Fig.
2.5
,Raweetal.
2002
).
The first births in this condition were reported by Porcu et al. (
2003
) and, more recently,
two successful ICSI attempts in one of our patients were followed by pregnancies and
births of healthy children (Coco et al., manuscript in preparation). These dissimilar
results indicate variations in the degree of abnormalities of the head-neck junction,
some of them compatible with normal centrosomal function.
Various observations have demonstrated the ultrastructural integrity of proxi-
mal centrioles in spermatozoa with defects of the head-tail attachment (Baccetti
et al.
1989
; Chemes et al.
1999
). In the search for the nature of this centrosome
abnormality we realized that there was dissociation between the function of both
centrioles. While distal centrioles successfully completed development of flagellar
axonemes, proximal centrioles were unable to attach normally to spermatid nuclei
and failed to reconstitute zygotic centrosomes. This type of functional dissociation
between both centrioles has its counterpart in PCD (Primary Ciliary Diskinesia or
Immotile Cilia Syndrome) where the function of proximal centrioles is preserved
(immotile PCD spermatozoa fertilize oocytes when microinjected) while distal
centrioles generate abnormal sperm axonemes. This double function and dissoci-
ated pathology is an interesting dualistic model underscoring a high degree of
autonomy between proximal and distal centrioles.
