Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF)

Abstract

Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare disease that causes primary infertility. However, the genetic causes for approximately half of MMAF cases are unknown. Whole exome sequencing analysis of the 27 patients with MMAF identified several CFAP44 mutations (3 homozygous: c.2935_2944del: p.D979*, c.T1769A: p.L590Q, c.2005_2006del: p.M669Vfs*13; and putative compound heterozygous: c.G3262A: p.G1088S and c.C1718A: p.P573H.) and CFAP43 acceptor splice-site deletion (c.3661-2A>-) mutations in 5 and 1 patients, respectively. Real-time quantitative polymerase chain reaction assays also demonstrated that CFAP44 expression was very weak in patient (P)1 and P3, and CFAP43 expression was lower in P6 than in the control. Immunofluorescence analysis of CFAP43 showed lower CFAP43 protein expression levels in P6 than in the normal control. This study demonstrated that biallelic mutations in CFAP44 and CFAP43 cause MMAF. These results provide researchers with a new insight to understand the genetic etiology of MMAF and to identify new loci for genetic counselling of MMAF.

Keywords

multiple morphological abnormalities of the sperm flagella MMAF CFAP44 CFAP43 consanguineous family whole exome sequencing dysplasia of the fibrous sheath

Get full access to this article

View all access options for this article.

References

Ben Khelifa

Coutton

Zouari

. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94(1):95–104.

Barthelemy

Tharanne

Lebos

Lecomte

Lansac

. Tail stump spermatozoa: morphogenesis of the defect. An ultrastructural study of sperm and testicular biopsy. Andrologia. 1990;22(5):417–425.

Rawe

Galaverna

Acosta

Olmedo

Chemes

. Incidence of tail structure distortions associated with dysplasia of the fibrous sheath in human spermatozoa. Hum Reprod. 2001;16(5):879–886.

Chemes

Brugo

Zanchetti

Carrere

Lavieri

. Dysplasia of the fibrous sheath: an ultrastructural defect of human spermatozoa associated with sperm immotility and primary sterility. Fertil Steril. 1987;48(4):664–669.

Ross

Christie

Edmond

. Ultrastructural tail defects in the spermatozoa from two men attending a subfertility clinic. J Reprod Fertil. 1973;32(2):243–251.

Sha

Yang

Mei

. DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the han chinese population. Fertil Steril. 2017;107(6):1312–1318.e2.

Afzelius

Eliasson

. Flagellar mutants in man: on the heterogeneity of the immotile-cilia syndrome. J Ultrastruct Res. 1979;69(1):43–52.

Wang

Jin

Han

. Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in chinese. Clin Genet. 2017;91(2):313–321.

Amiri-Yekta

Coutton

Kherraf

. Whole-exome sequencing of familial cases of multiple morphological abnormalities of the sperm flagella (MMAF) reveals new DNAH1 mutations. Hum Reprod. 2016;31(12):2872–2880.

10.

Tang

Wang

. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2017;100(6):854–864.

11.

Baccetti

Collodel

Estenoz

Manca

Moretti

Piomboni

. Gene deletions in an infertile man with sperm fibrous sheath dysplasia. Hum Reprod. 2005;20(10):2790–2794.

12.

Sha

. TSGA10 is a novel candidate gene associated with acephalic spermatozoa [Epub ahead of print.]. Clin Genet. 2017.

13.

Sha

Mei

. A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF). Gene. 2017;633:48–53.

14.

Kee

Angeles

Flores

Nguyen

Reijo Pera

Human

DAZL

. DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature. 2009;462(7270):222–225.

15.

Merveille

Davis

Becker-Heck

. CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. 2011;43(1):72–78.

16.

Pedersen

Rompolas

Christensen

Rosenbaum

King

. The lissencephaly protein lis1 is present in motile mammalian cilia and requires outer arm dynein for targeting to chlamydomonas flagella. J Cell Sci. 2007;120(pt 5):858–867.

17.

Hendrickson

Perrone

Griffin

. IC138 is a WD-repeat dynein intermediate chain required for light chain assembly and regulation of flagellar bending. Mol Biol Cell. 2004;15(12):5431–5442.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.38 MB