Download Fine mapping of re-arranged Y chromosome in three infertile

doi:10.1093/humrep/dem127
Human Reproduction Vol.22, No.7 pp. 1854–1860, 2007
Fine mapping of re-arranged Y chromosome in
three infertile patients with non-obstructive
azoospermia/cryptozoospermia
A.K. Faure1,2,3, I. Aknin-Seifer4, V. Satre3, F. Amblard3, F. Devillard3, S. Hennebicq1,2,3,
J. Chouteau5, U. Bergues3, R. Levy4 and S. Rousseaux1,2,3,6
1
INSERM, U823, Grenoble F-38706, France; 2Université Joseph Fourier, Institut Albert Bonniot, Grenoble F-38706, France;
Département de Génétique et Procréation, CHU de Grenoble BP 217, 38 043 Grenoble Cedex 09, France; 4Laboratoire de Biologie de
la Reproduction et/ou service de Génétique Moléculaire, Hôpital Nord, 42 055 Saint Etienne, France and 5Clinilab, 38 400 Saint Martin
d’Hères, France
3
6
Correspondence address. Tel: þ33-4-76-54-95-12; Fax: þ33-4-76 –54-95-95; E-mail: [email protected]
BACKGROUND: Cytogenetically detectable aberrations of the Y chromosome, such as isodicentrics, rings or translocations are sometimes associated with male non-obstructive infertility. This report presents a detailed analysis of the
clinical, cytogenetic and molecular data in three patients with a re-arranged Y chromosome. METHODS: Patients A
and B were azoospermic, whereas patient C was cryptozoospermic. All had a somatic mosaic karyotype including
a population of 45,X cells and a cell line with a re-arranged Y chromosome. A molecular and FISH analysis of their
re-arranged Y was undertaken, which specifically focussed on the presence of the AZFa, b and c regions. RESULTS:
The AZFa region was present in all the three patients. The AZFb and AZFc regions were absent in patients A and B,
whereas, in patient C, the distal part of AZFb and the whole AZFc region were deleted. Moreover, in this patient,
the AZF FISH analysis revealed a mosaicism for the size of the AZF deletion within the re-arranged Y, suggesting
a progressive enlargement of the deletion during cell mitotic divisions. CONCLUSIONS: This investigation allowed
not only a more precise description of the abnormal Y, but also shed light on how this re-arrangement could be
involved in the infertility phenotype.
Keywords: azoospermia/Y deletion/sex chromosomes/chromosomal abnormalities
Introduction
Y microdeletions, generally resulting from intrachromosomal
recombination events between large homologous repetitive
sequence blocks in Yq11, are the most frequent known genetic
cause of non-obstructive severe oligozoospermia or azoospermia, with a frequency ranging from 10% to 15% (Krausz,
2005; Kuroda-Kawaguchi, 2001; Noordam and Repping, 2006).
Among cytogenetically detectable aberrations of the
Y chromosome, the isodicentric Y, idic(Y), is the most
common. It results from a break occurring in the juxtacentromeric region, followed by the duplication of the centromerecontaining fragment of the chromosome. They can sometimes
be mistaken for a normal Y chromosome by the routine Giemsa
staining procedure, because of their similarity in size compared
to the normal Y chromosome (Siffroi et al., 2000). A ring
chromosome, r(Y), can also be associated with male infertility.
It results from the fusion of the two broken short and long
arms of a Y chromosome, forming a circular configuration
(Tharapel, 2005).
1854
This report presents a detailed analysis of the clinical, cytogenetic and molecular data in three patients with a re-arranged
Y chromosome.
Materials and Methods
Clinical reports
Patients A and B were azoospermic, whereas patient C was cryptozoospermic. Their clinical and biological parameters are described
in Table 1. They were all mosaics with two different cell lines. One
of the cell populations is monosomic (45,X) whereas the second
contains 46 chromosomes with a re-arranged Y.
Karyotyping and SRY FISH analysis
Chromosome analysis was performed on peripheral blood metaphases
using the standard techniques and R, G and, in some cases, C banding.
FISH studies were performed to assess the presence or absence of the
SRY gene (LSI SRY (Yp11.3)) (Vysis, IL, USA).
# The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
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AZF regions in re-arranged Y chromosomes
Table 1: Clinical and biological characteristics, and results of the AZF region analysis (by STS and FISH) of the three studied patients
Patient A
Patient B
Patient C
Clinical data
Age (years)
Height (cm)
Weight (Kg)
Duration of infertility (years)
Exposure to toxics or tobacco
History of urological problems
Clinical examinationa
36
178
70
0.5
Tobacco (15 years)
No
Nl
32
164
64
2
No
No
Nl excepted reduced testis
volume (5– 10 ml)
39
157
65
5
Tobacco
No
Nl
Biological investigations
Sperm parameters
FSH (IU/l)
LH (IU/l)
Inhibin B
Testosterone (nmol/ml)
Testicular biopsy (Histology)
Initial karyotype
Azoospermia
Elevated
Elevated
Undetectable
Free: 1.83 (Normal range: 2 –9)
SCO
45,X[14]/46,X,idic(Y)[86]
Azoospermia
Nl
Nl
ND
Total: Nl
ND
45,X[83]/46,X,idic(Y)[31]
Very few immotile s.p.z.
Nl
ND
Nl
ND
ND
45,X[10]/46,X,r(Y)[89]/
47,X,r(Y),þr(Y) [1]
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
STS analysis of the three AZF regions (buccal cells)
ZFY
þ
SRY
þ
AZFa
sY82
þ
sY83
þ
sY86
þ
sY84
þ
sY87
þ
sY88
þ
sY95
þ
AZFb
sY117
sY114
sY1015
sY127
sY1211
sY1207
sY134
sY135
sY143
sY142
sY145
sY1197
2
2
2
2
2
2
2
2
2
2
NA
Weakþ
2
2
2
2
NA
NA
2
2
2
2
2
NA
þ
þ
þ
þ
þ
þ
þ
þ
2
2
2
2
AZFc
sY1192
sY152
sY149
sY254
sY255
sY158
sY157
sY1125
2
2
NA
Weakþ
Weakþ
Weakþ
Weakþ
Weakþ
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
27/27
NA
NA
67/67
41/47
0/61
FISH analysis of the three AZF regions (blood metaphases)
AZFa detectionb
55/56
0/93
AZFb detectionb
0/100
AZFc detectionb
Nl, normal; ND, not defined; s.p.z., spermatozoa; SCO, Sertoli cells only syndrome (the testis histology showed a majority of empty tubules with a thickening of
the basement membrane, and a few Sertoli cell-only tubules); þ, STS present; 2, STS absent (The studied STS were all positive in a control male—not
shown); NA, not analysed.
a
Clinical examination included the evaluation of secondary sexual characteristics, the examination of excretory ducts (epididymis, prostate and seminal vesicles),
as well as evaluation of testis volume.
b
Number of positive metaphases with each AZF probe/number of 46,XY metaphases analysed.
Molecular analysis of the AZF regions
STS analysis was performed on genomic DNA extracted from buccal
cells using the International Recommendations (Fig. 1) (Simoni et al.,
2004). For a first screening, eight STS were analysed in two multiplex
PCRs: sY84 and sY86 for AZFa, sY127 and sY134 for AZFb, sY254
and sY255 for AZFc. SRY (sY14) and ZFY were included as internal
positive controls. All deleted samples were subjected to a complementary screening using 18 STS in nine duplex experiments: sY82, sY83,
sY87, sY88, sY95, sY117, sY114, sY1015, sY135, sY143, sY142,
sY145, sY1197, sY1192, sY152, sY158, sY157, sY1125. Several
1855
Faure et al.
Figure 1: Cytogenetic and in situ mapping of re-arranged Y chromosomes. (A) Respective positions of the STS and BAC clones used for the Y
mapping in the three azoospermic/cryptozoospermic patients. (B) X and Y chromosomes (R banding) in patients A, B and C, respectively. (C)
Codetection of each AZF region (green) and the Y centromere (red) by FISH on metaphases of patient A. The AZFa region was present on all but
one Y chromosomes of patient A (n ¼ 55 metaphases), whereas AZFb and AZFc were always absent (n ¼ 93 and 100 metaphases, respectively)
controls were used for each PCR: a blank without DNA, a female
DNA, a male DNA with a known AZFc deletion, as well as a fertile
male DNA.
AZF FISH experiments
FISH experiments were performed on metaphases using probes cloned
in Bacterial artificial chromosome (BAC) vectors. Each probe was,
respectively, specific for the three AZF a, b and c, regions on Yq.
The BACs were chosen from the RP11 library according to the
mapping of Tilford and collaborators (Tilford et al., 2001), and provided by the Wellcome Trust Sanger Institute (Cambridge, UK)
(http://www.sanger.ac.uk/). They were as follow: BAC clone
RP11-492N16 for the AZFa region, BAC clone RP11-424G14 for
the AZFb region, and BAC clone RP11-539D10 for the AZFc
region (Fig. 1A). The DNA were extracted from the BACs, labelled
and hybridized according to standard protocols.
The localization and identification of the Y chromosome was confirmed by co-hybridization of each AZF probe with a probe specific
for the Yp11.1–q11.1 a-satellite region (CEP Y alpha (DYZ3)
(named thereafter ‘centromeric probe’) (Vysis, IL, USA).
On metaphase chromosomes of control fertile patients, all three
probes displayed a strong spot-like signal on each chromatid, which
localized exclusively to the proximal part of the long arm of the Y
chromosome, whereas, as expected, no signal was observed when
they were hybridized on metaphases of infertile patients with a
deletion of the AZFa, AZFb or AZFc region.
Results
The results of these investigations are detailed in Table 1 and
Fig. 1B and C. For both patients A and B, the initial somatic
1856
karyotype showed a mosaicism, including a 45,X cell line
and a 46,X,i(Y)(p10). The AZF STS analysis on their buccal
cells showed that a part of the long arms of the Y chromosome
was actually present on the ‘isochromosome’ of both patients,
since all AZFa markers were positive. However the AZFb þ c
markers were absent. The AZFa FISH analysis confirmed this
observation since it was positive on the Y re-arranged chromosomes in almost all the 46,XY metaphases analysed (55/56 in
patient A and 27/27 in patient B). Somatic karyotypes were
therefore redefined as follow: 45,X[14]/46,X,idic(Y)(pter- .
q11.23::q11.23- . pter)[86].ishYp11.3(SRYx2) for patient A,
and 45,X[83]/46,X,idic(Y)(pter- . q11.23::q11.23- . pter)
[31].ish Yp11.3 (SRYx2) for patient B.
In patient C, the initial somatic karyotype showed that, in
10% of the mitosis, the Y chromosome was lost, whereas in
90% of the mitosis, one or two copies of a Y ring chromosome
were detected. An initial FISH analysis with alpha-satellites
probes of the centromere and the Yp11.3 (SRY) region
showed that the ring Y chromosome breakpoints were located
in p11.3 on the short arm, and q11 on the long arm. The STS
analysis showed the presence of the AZFa region and a deletion
including the distal part of AZFb and the whole AZFc region
(Table 1). The Yq11 breakpoint could therefore be located in
the distal part of the AZFb region. The AZF FISH analysis
not only confirmed this result but also suggested a sequential
increase of the Y deletion (Table 1). Indeed, in the AZFb
FISH experiment, among the 46,XY metaphases positive for
the centromeric probe (n ¼ 47), 41 (87%) were positive for
AZFb and 6 (13%) were negative.
Table 2: Other cases of patients reported in the literature with a re-arranged and deleted Y chromosome associated with a somatic mosaicism
Reference
Somatic karyotype (lymphocytes)
AZF deletion (PCR)
Sry gene
Male (M) or
Female (F)
phenotype
Gonad abnormalities and fertility data
Henegariu et al. (1997)
45,X[5]/46,X,r(Y)[39]
AZFaþbþc
NA
M
Tzancheva et al. (1999)
45,X[5]/46,X,r(Y)[92]/
47,X,r(Y),þr(Y)[3]
45,X[36]/46,X,idic(Y)[64]
AZFaþbþc
NA
Mb
Gonadal dysgenesis (testicular tubules and foci of ovarian-like
stroma, absence of germ cells), Cryptorchidism, hypospadia
Azoospermia, small testes
AZFc
NA
Fb
AZFbþc
AZFbþc
DAZ-
NA
NA
þ
M
M
F
AZFaþbþc
þ
Fb
Primary amenorrhea, Uterine hypoplasia, streak gonads
Partial AZFbþAZFc
þ
M
Cryptorchidism
Partial AZFbþAZFc
Partial AZFbþAZFc
Partial AZFbþAZFc
Partial AZFbþAZFc
AZFbþc
Partial AZFbþAZFc
Partial AZFaþAZFbþc
AZFbþc
NA
NA
NA
NA
NA
þ
NA
þ
M
M
M
M
Fb
M
M
M
Fertility unknown, normal male genitalia
Azoospermia, cryptorchidism
Azoospermia
Azoospermia
Bilateral streak gonads
Unknown
Azoospermia
Azoospermia, small testes
Partial AZFbþAZFc
Partial AZFbþAZFc
AZFaþbþc
NA
þ
þ
M
M
M
AZFc
NA
Fb
Azoospermia
Azoospermia, small testes
Azoospermia, Small testes, left varicocele and epididymis
enlargement
Streak gonads
AZFc
NA
Fb
Streak gonads
Godoy Assumpcao et al.
(2000)
Siffroi et al. (2000)
Giltay et al. (2001)
Stankiewicz et al. (2001)
Hernando et al. (2002)
Quilter et al. (2002)
Brisset et al. (2005)
Bertini et al. (2005)
Patsalis PC et al. (2005)
1857
45,X[70]/46,X,idic(Y)[20]/
47,X,idic(Y),þidic(Y)[10]
45,X[91]/46,X,idic(Y)[6]/47,
X,idic(Y),þidic(Y)[3]
Continued
AZF regions in re-arranged Y chromosomes
Yoshitsugu et al. (2003)a
Lin et al. (2004)
Valetto et al. (2004)
45,X/46,X,idic(Y)(q11.2)
45,X/46,X,idic(Y)(q11.2)
45,X,inv(10)(p11.2q21.2)[30]/
46,X,idic(Y)(q11.23),inv(10)[47]/
47,X,idic(Y)(q11.23)x2,inv(10)[5]
45,X[128]/46,X,þidic(Y)(p11.32)[65]/
47,XY,þidic(Y)(p11.32)[2]/
47,X,þ2idic(Y)(p11.32[1]
46,X,þi(Y)(p10)[23]/47,X,þidic(Y)
(q11.23),þi(Y)(p10)[77]
45,X[14]/46,X,idic(Y)(q11.2)[86]
45,X[64]/46,X,idic(Y)(q11.2)[36]
45,X[6]/46,X,idic(Y)(q11.2)[94]
45,X[5]/46,X,idic(Y)(q11.2)[3]
45,X[92]/46,X,del(Y)(q11.2)[8]
45,X[11]/46,X,idic(Y)(q11)[19]
45,X[9]/46,X,r(Y)(p11q11)[11]
45,X[71]/46,X,idic(Y)(q11)[26]/46,
XY[3]
45,X/46,X, der(Y)t(Y;22)(q11.2;q11.1)
45,X[8]/46,X,r(Y)[92]
45,X[5]/46,X,r(Y)[95]
Primary amenorrhea, Uterine hypoplasia, gonadal dysgenesis (left
streak gonad and right hypoplastic ovary)
Azoospermia
Azoospermia
Uterine hypoplasia, Left streak ovary and right ovary with
gonadoblastome
Faure et al.
1858
Table 2: Continued
Reference
Somatic karyotype (lymphocytes)
AZF deletion (PCR)
Sry gene
Male (M) or
Female (F)
phenotype
Gonad abnormalities and fertility data
Queipo G et al. (2005)
45,X[10]/46,X,idic(Y)[90]
45,X[20]/46,X,del(Y)[80]
45,X[80]/46,X,del(Y)[20]
45,X[8]/46,X,idic(Y)[74]
AZFbþc
AZFbþc
AZFaþbþc
AZFbþc
NA
NA
NA
þ
Fb
M
Fb
M
45,X[12]/46,X,idic(Y)(p10)[38]
45,X[17]/46,X,idic(Y)(p10)[33]
45,X[33]/46,X,idic(Y)(p10)[9]/
46,X,þmar[5]/
47,X,idic(Y)(p10),þmar[3]
45,X[27]/46,X,del(Y)(q11.23)[68]/
47,X,del(Y)(q11.23)[5]
AZFbþc
AZFbþc
AZFbþc
þ
þ
þ
M
M
M
Streak gonads
Azoospermia
Streak gonads
Gonadal dysgenesis (2 left testes and right streak gonad),
ambiguous genitalia, uterine hypoplasia
Hypoplastic uterus
Azoospermia, small testes/SCO
Azoospermia, small testes
Azoospermia, small testes/SCO, varicocele
AZFbþc
NA
M
Azoospermia, small testes, SCO
Bettio et al. (2006)
Cui et al. (2006)
NA, not analysed; DAZ, deleted in azoospermia gene; SCO, Sertoli cell-only syndrome.
Paranoid schizophrenia and mild mental retardation.
Turner or Bonnevie-Ullrich manifestations.
a
b
AZF regions in re-arranged Y chromosomes
Hence, combining the molecular and FISH analysis of
the AZF region, the initial karyotype of patient C was refined
as 45,X[10]/46,X,r(Y)(p11.3q11.23)[89]/47,X,r(Y), þ r(Y)
(p11.3q11.23)[1].ishr(Y)(p11.3q11.23) (DYZ3þ, SRYþ) and
a mosaicism for the size of the AZF deletion within the
46,X,r(Y) population, was evidenced.
Discussion
In the literature, most cases of Y rearrangements, including
idic(Y) and r(Y), are reported, as here, in a mosaic form,
usually in association with a 45,X cell line. Other cases of patients
with re-arranged and AZF-deleted Y chromosome associated
with a somatic mosaicism of the sex chromosomes are summarized in Table 2. The associated sex chromosomes mosaicism is
likely due to the instability of the re-arranged Y, which can be
lost through cell divisions (Alvarez-Nava and Puerta, 2006;
Patsalis et al., 2005; Siffroi et al., 2000). The proportion of
45,X cells is highly variable between individuals, ranging
from 1% to 90%, and can also differ between the different
cell lineages within the same individual. These mosaic karyotypes are associated with a wide spectrum of clinical phenotypes, ranging from male infertility with normal sexual
characteristics, ambiguous external genitalia, or female with
typical or atypical Turner syndrome (Alvarez-Nava et al.,
2003; DesGroseilliers et al., 2006; Le Bourhis et al., 2000).
A simple relationship between the percentage of 45,X cells
among blood lymphocytes and the patient’s phenotype has not
been found. In the present study, the three patients all shared a
normal male phenotype, despite the high level of 45,X cell
lines observed in patient B.
An important issue regarding infertile male carriers of a
re-arranged Y is the relationship between the abnormal Y
and the infertility phenotype. Here, the presence or absence
of one or more of the three AZF regions is of crucial
importance.
This study provides the first FISH analysis of the AZF
regions in patients with complex sex chromosome mosaicism.
In patient C, a mosaicism for the AZFb deletion was found in
six metaphases (13%) among the 47 analysed. This result is of
great interest, as it suggests that the instability of the Y deleted
chromosome, could also be involved in an extension of the
deletion during cell divisions, and possibly in the transmission
of a larger deletion to the next generation. This variation in the
size of AZF deletion could be the result of the particular behavior of the ring chromosomes during mitosis. Indeed, the
occurrence of sister chromatid exchanges could result in the
formation of dicentric ring chromosomes, which would then
undergo unequal partition during successive mitotic divisions
inducing the formation of rings of different sizes (Miller and
Therman, 2001).
Acknowledgements
We would like to gratefully acknowledge Roberte Pelletier and
Christine De Robertis for their technical expertise. A.K.F. was recipient of a grant of ‘Poste d’accueil INSERM’ and SR of a ‘contrat
d’interface’ INSERM. We wish to thank the Chromosome Y
Mapping Core group of the Sanger Institute (Cambridge, UK)
(http://www.sanger.ac.uk/) for providing the BAC clones used in
this study, and Drs Stora de Novion and J. Lespinasse for their contribution to the biological data of the patients.
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Submitted on January 9, 2007; resubmitted on March 11, 2007; accepted on
April 11, 2007