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Table 2 Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities

From: Genes predisposing to syndromic and nonsyndromic infertility: a narrative review

SPATA16 (spermatogenesis-associated 16, also known as NYD-SP12) 3q26.32 The gene is expressed mainly in the Golgi apparatus of the cells of testis [69] and actively involved in the formation of sperm acrosome, which plays a role in spermatogenesis and fusion of sperms and eggs [70]. A homozygous SNP in exon 4 named c.848G → A was reported [17]. Causes acrosome malformation which can be absent in severe cases, resulting in sperm head abnormality characterized by round-headed sperms known as globozoospermia [71]. Also predisposes spermatogenic failure 6 (SPGF6), an infertility disorder caused by spermatogenesis defects [70].
AURKC (aurora kinase C) 19q13.43 The AURKC codes for a protein called aurora kinase, which helps dividing cells separate from each other and ensures the accurate distribution of genetic materials (chromosomes). Aurora kinase C is most abundant in male testes, where it regulates the division of sperm cells, ensuring that every new sperm cell divides accurately and contains one copy of each chromosome [72]. A homozygous deletion called c. 144delC and frequently found among North African descent was reported [72]. Produces a nonfunctional aurora kinase C or a protein that breaks down quickly, preventing sperm cell division. Consequently, the sperm cells carry extra chromosomes (polyploidy spermatozoa), usually four copies of each instead of the usual one. The increase in chromosome number enlarges the sperm cell head and leads to the presence of multiple tails (flagella), a condition called macrozoospermia. The additional genetic materials may prevent any of the sperm cells from fusing with an egg or may result in miscarriage [72].
CATSPER (cation channel sperm associated 1) 11q13.1 The gene encodes a protein localized in the tail of sperm cells and transport calcium cations into the cells for normal sperm motility and a type of sperm cell motility called hyperactivation, which is a rigorous movement necessary to push the sperm cells through the cell membrane of the egg cell during fertilization [73]. Two insertion mutations named c.539-540insT and c.948-949insATGGC, leading to frameshifts and premature stop codons known as p.Lys180LysfsX8 and p.Asp317MetfsX18, have been reported [74]. Alters or malfunctions CATSPER1 protein or produces a protein that is degraded quickly by the cell. This impairs calcium entry into the sperm cell, decreasing the motility and preventing hyperactivation, ultimately resulting in CATSPER1-related non-syndromic male infertility. Affected men may also produce a smaller than the usual number of sperm cells or sperm cells that are abnormally shaped [73].
MTHFR (methylenetetrahydrofolatereductase) 1p36.22 The MTHFR gene synthesizes an enzyme called methylenetetrahydrofolate reductase, which converts a form of folate called 5, 10-methylenetetrahydrofolate to an another form called 5-methyltetrahydrofolate. The latter is the primary form of folate in the blood, where it helps converts the amino acid homocysteine to another amino acid called methionine. The body uses methionine to make proteins and other important compound as well as vital in DNA methylation and spermatogenesis [75, 76]. A SNP named 677C/T and involving the substitution of an alanine for a valine is the most common in infertile men with MTHFR deficiency [13]. The second mutation involved an A to C transition at nucleotide 1298 (A1298C), resulting in glutamate to alanine substitution in the MTHFR protein [77]. Loss of MTHFR decreases the activity of its enzyme, disrupting folic acid metabolism, resulting in DNA hypo-methylation, ultimately ending in the absence of germinal cells and spermatogenesis arrest [13, 75, 78].
SYCP3 (synaptonemal complex protein 3) 12q23.2 SYCP3 is embedded in the testis and encoded an essential structural component of the synaptonemal complex, which is involved in synapsis, recombination, and segregation of meiotic chromosomes [79]. The gene ensures centromere pairing during meiosis in male germ cells, thus important for normal spermatogenesis [80]. A heterozygous deletion called 643delA, and a heterozygous genetic change known as T657C was identified among Iranian women with recurrent pregnancy losses [17]. Causes early meiotic arrest, disrupting the spermatogenic process in males [17], resulting in spermatogenic failure 4 (SPGF4), a disorder characterized by azoospermia. In females, early meiotic arrest causes recurrent pregnancy loss [79].
HSF2 (heat-shock transcription factor 2) 6q22.31 HSF2 is expressed in the testis and encodes heat-shock transcription factor 2, which binds specifically to the heat-shock promoter element to activate heat-shock response genes under conditions of heat or other stresses [81]. Heterozygous missense mutations have been reported [82]. HSF2-null male mice showed embryonic lethality, neuronal defects, and reduced spermatogenesis that relates to meiotic arrest, increased sperm apoptosis, and seminiferous tubule dysgenesis [83]. Male humans showed azoospermia [82].
SYCP2 (synaptonemal complex protein 2) 20q13.33 The gene codes for a major component of the synaptonemal complex, which is required for normal meiotic chromosome synapsis during oocyte and spermatocyte development and for normal male and female fertility [84]. Heterozygous frameshift mutation and deletion have been reported in the gene [85]. Alters synaptonemal complex, disrupting spermatogenesis and resulting in cryptozoospermia and azoospermia [85, 86].
A-MYB/MYBL1 (myeloblastosis oncogene-like 1) 8q13.1 MYBL1 protein is a male-specific master regulator of meiotic genes that are involved in multiple processes in spermatocytes, particularly processes involved in cell cycle progression through pachynema [87]. A variant named repro9 involving a C to A transversion at nucleotide 893 of the MYBL1 mRNA was reported [87]. MYBL1−/−, showing meiotic arrest similar to repro9, has also been reported [87]. Causes meiotic arrest in spermatocytes, characterized by defects in autosome synapsis in pachynema, unsynapsed sex chromosomes, incomplete double-strand break repair on synapsed pachytene chromosomes and a lack of crossing over [87].
TEX11 (testis expressed 11) Xq13.1 TEX11 protein is required for spermatogenesis; particularly certain levels of the protein are required for meiotic progression. The protein is also necessary for normal genome-wide meiotic recombination rates in both sexes [88]. Frameshift mutations were observed, so also missense mutations, particularly a missense mutation tagged V748A was observed among transgenic mice [88]. Causes meiotic arrest in male mice, resulting in spermatogenic failure, X-linked, 2 (SPGFX2), a disorder characterized by mixed testicular atrophy and azoospermia [89]. Among humans, meiotic arrest leads to non-obstructive azoospermia [88].
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) 4q12 The gene is embedded in the reproductive cells and encoded receptor tyrosine kinases, which is involved in signal transduction. The protein takes part in phosphorylation that activates a series of proteins in multiple signaling pathways, which are necessary for normal cell growth, proliferation, survival, and movement in the reproductive cells and certain other cell types [90]. A SNP in which Asp-816 is replaced with a Val or His residue at exon 17 has been reported [91]. Causes seminomas and testicular carcinoma [91].
ADGRG2 (adhesion G protein-coupled receptor G2) Xp22.13 This gene encodes an epididymis-specific transmembrane protein, which is involved in a signal transduction pathway controlling epididymal function and male fertility. May particularly regulate fluid exchange within the epididymis [92]. Three protein-truncating hemizygous mutations, named c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), have been reported [93]. Predisposes to congenital bilateral aplasia of the vas deferens, X-linked (CBAVDX), a disease characterized by bilateral absence of vas deferens and obstructive azoospermia [92].
FKBP6 (FKBP prolylisomerase 6) 7q11.23 Encodes a protein that functions in immunoregulation, homologous chromosome pairing in meiosis during spermatogenesis and cellular processes involving protein folding and trafficking [94]. Deletion in the exon 8 of the gene has been reported [95]. Causes spermatogenic failure, resulting in azoospermia or severe oligozoospermia [96].
PRM1 (protamine 1) 16p13.13 It encodes a protein called protamine 1, which replaces histone during developmental stages of elongating spermatids and compact sperm DNA into a highly condensed, stable, and inactive complex to ensure that quality spermatozoa are produced and as well protect spermatozoa from the degrading effects of free radicals [97]. A c.102G>T transversion that results in the SNP named p.Arg34Ser, a missense mutation named c.119G>A (p.Cys40Tyr), a heterozygous mutation named c.-107G>C, and a variant named c.*51G>C have been reported [98]. Increases sperm DNA fragmentation, resulting in oligozoospermia [98].
PRM2 (protamine 2) 16p13.13 PRM2 secretes protamine 2, which replaces histone during spermatid development, condensing chromatin, and compacting the DNA to ensure production of quality spermatozoa and prevent degradation by free radicals [97]. A SNP, known as -190C > A (rs2301365), was identified in both PRM1 and 2 [99]. Causes chromatin damage and DNA breaks, resulting in sperm structural defects, reduced motility, and defective spermatogenesis due to haploinsufficiency [100].
TNP1 (nuclear transition protein 1) 2q35 The gene encodes nuclear proteins, which replace nuclear histones and in turn substituted by protamine 1 and 2 during spermatogenesis [101]. A SNP named g.IVS1+75T>C was reported by Heidan et al [102]. A deletion of 15 nucleotides in the 5′-promoter region of the gene was also reported [101]. Disrupts the highly condensed structure of the sperm nuclear chromatin, resulting in abnormal spermatogenesis [102]. Also causes varicocele, due to the failure of ipsilateral testicular growth and development [102].
TNP2 (nuclear transition protein 2) 16p13.13 TNP2 participates in the removal of the nucleohistones and in the initial condensation of the spermatid nucleus, thus contributes to the dense packing of spermatid chromatin during spermatogenesis [103]. A variant named G1272C was reported [98]. TNP2−/− in mice affects sperm chromatin structure, causing sperm head abnormalities, acrosome abnormalities in which the acrosomes do not attach to the nuclear envelope, and reduced sperm motility, resulting in tetrazoospermia [103].
DAZ1 (deleted in azoospermia 1) Yq11.223 The gene encodes azoospermia protein 1, which is necessary for spermatogenesis. It binds to the 3′-UTR of mRNAs, regulating their translation, and promoting germ cell progression to meiosis and the formation of haploid germ cells [104]. DAZ1 deletions were reported [105]. Causes Y chromosome infertility known as spermatogenic failure Y-linked 2 (SPGFY2), a disorder resulting in azoospermia or oligozoospermia [104]. Also causes sperm structural abnormalities and reduced motility [106].
XRCC2 (X-ray repair cross complementing 2) 7q36.1 XRCC2 protein was shown in mice to be required for genetic stability, embryonic neurogenesis and viability [107]. A SNP in the gene involving c.41T>C substitution was reported [108]. Causes meiotic arrest, resulting in azoospermia [108].
CCDC62 (coiled-coil domain containing 62) 12q24.31 Encodes a nuclear receptor co-activator that enhances estrogen receptor transactivation [109]. The gene is expressed in the acrosome of developing spermatids and mature sperms, showing that it is necessary for spermatogenesis [110]. A nonsense mutation in the exon 6, which results in the formation of a premature stop codon and a truncated protein, was reported by Li et al. [110]. Causes defective sperm morphology and reduced motility [110].
EFCAB9 (EF-hand calcium21 binding domain-containing protein 9) 5q35.1 Encodes sperm-specific EF-band domain protein, which is essential for activation of CATSPER channel that regulates sperm motility [111]. EFCAB9 deletions were reported [111]. Disrupts CATSPER channel signaling, which affects sperm motility [111].
KLHL10 (Kelch-like family member 10) 17q21 KLHL10 encodes a germ cell-specific protein essential for spermatogenesis [63]. Two missense mutations named A313T and Q216P were reported [112]. Impairs homodimerization, resulting in germ cell loss, abnormal spermatids, and severe oligozoospermia [112].
SEPT12 (septin 12) 16p13.3 The gene codes for septin 12, which is expressed exclusively in the testis and involved in spermatogenesis, especially morphogenesis of sperm heads and the elongation of sperm tails [63]. Two missense mutations named c.266C>T/p.Thr8 Met and c.589G>A/p.Asp197Asn were reported by Kuo et al. [113]. Disrupts the structural integrity of sperm by perturbing septin filament formation, causing various sperm abnormalities, including immotility, bent tails, acrosome breakage, round heads, and significant spermatozoa DNA damage, as well as oligoasthenozoosperm and asthenoteratozoospermia [63, 113].
TAF4B (TATA-box binding protein associated factor 4b) 18q11.2 TAF4B encodes a transcriptional coactivator and involved in folliculogenesis, spermatogenesis, and oogenesis [114]. A nonsense mutation in exon 9 named p.R611X was reported [115]. Causes spermatogenic failure 13 (SPGF13), a disorder resulting in azoospermia or oligozoospermia [114].
ZMYND15 (zinc finger mynd-containing protein 15) 17p22.1 ZMYND15 codes for a transcription repressor, which in mice is expressed exclusively in the haploid germ cells, particularly during late spermatogenesis [116]. A mutation in exon 9 of the gene named p.K507Sfs*3 was reported by Ayhan et al. [115]. Causes spermatogenic failure 14 (SPGF14), a disorder resulting in azoospermia or oligozoospermia [117].
NANOS1 (nanos C2HC-type zinc finger 1) 10q26.11 This gene encodes a CCHC-type zinc finger protein that is specifically expressed in the germ cells of adult men and regulates the translation by acting as a post-transcriptional repressor [118]. Two deletion mutations called p.Pro77_Ser78delinsPro and p.Ala173del have been reported [119]. Results in spermatogenic failure 12 (SPGF12), an infertility disorder caused by spermatogenesis defects, characterized by decreased sperm motility and concentration, sperm structural defects, non-obstructive azoospermia, oligozoospermia, and oligo-astheno-teratozoospermia [120].
GALNTL5 (polypeptide N-acetylgalactosaminyltransferase Like 5) 7q36.1 GALNTL5 encodes an inactive protein, which is expressed in the testis and is required during spermatid development in which it participates in protein loading into the acrosomes [121]. Heterozygous single nucleotide deletion of maternal inheritance was reported [63, 122]. Decreases glycolytic enzymes, which disrupts protein loading into acrosomes, resulting in asthenozoospermia and poor sperm motility [122].