Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombination involving two recombination hotspots.
To date, mutations in two genes, SPATA16 and DPY19L2, have been identified as responsible for a severe teratozoospermia, namely globozoospermia. The two initial descriptions of the DPY19L2 deletion lead to a very different rate of occurrence of this mutation among globospermic patients. In order to better estimate the contribution of DPY19L2 in globozoospermia, we screened a larger cohort including 64 globozoospermic patients. Twenty of the new patients were homozygous for the DPY19L2 deletion, and 7 were compound heterozygous for both this deletion and a point mutation. We also identified four additional mutated patients. The final mutation load in our cohort is 66.7% (36 out of 54). Out of 36 mutated patients, 69.4% are homozygous deleted, 19.4% heterozygous composite and 11.1% showed a homozygous point mutation. The mechanism underlying the deletion is a non-allelic homologous recombination (NAHR) between the flanking low-copy repeats. Here, we characterized a total of nine breakpoints for the DPY19L2 NAHR-driven deletion that clustered in two recombination hotspots, both containing direct repeat elements (AluSq2 in hotspot 1, THE1B in hotspot 2). Globozoospermia can be considered as a new genomic disorder. This study confirms that DPY19L2 is the major gene responsible for globozoospermia and enlarges the spectrum of possible mutations in the gene. This is a major finding and should contribute to the development of an efficient molecular diagnosis strategy for globozoospermia.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de Santé et de Recherche Médicale (INSERM) U964, Centre National de Recherche Scientifique UMR1704, Université de Strasbourg, Illkirch 67404, France.
Elias
E
Elinati
Paul
P
Kuentz
Claire
C
Redin
Sara
S
Jaber
Frauke
F
Vanden Meerschaut
Joelle
J
Makarian
Isabelle
I
Koscinski
Mohammad H
MH
Nasr-Esfahani
Aygul
A
Demirol
Timur
T
Gurgan
Noureddine
N
Louanjli
Naeem
N
Iqbal
Mazen
M
Bisharah
Frédérique Carré
FC
Pigeon
H
H
Gourabi
Dominique
D
De Briel
Florence
F
Brugnon
Susan A
SA
Gitlin
Jean-Marc
JM
Grillo
Kamran
K
Ghaedi
Mohammad R
MR
Deemeh
Somayeh
S
Tanhaei
Parastoo
P
Modarres
Björn
B
Heindryckx
Moncef
M
Benkhalifa
Dimitra
D
Nikiforaki
Sergio C
SC
Oehninger
Petra
P
De Sutter
Jean
J
Muller
Stéphane
S
Viville
D017353:Gene Deletion; D059765:Homologous Recombination; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D017354:Point Mutation; D012091:Repetitive Sequences, Nucleic Acid
C511317:DPY19L2 protein, human; D008565:Membrane Proteins