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CATSPER-Related Male Infertility

, PhD, , PhD, and , MD.

Author Information

Initial Posting: ; Last Update: March 23, 2017.

Summary

Clinical characteristics.

CATSPER-related male infertility results from abnormalities in sperm and can be either CATSPER-related nonsyndromic male infertility (NSMI) or the deafness-infertility syndrome (DIS) when associated with non-progressive prelingual sensorineural hearing loss. Males with NSMI have infertility while females have no symptoms. Males with DIS have both infertility and hearing loss, while females have only hearing loss. Routine semen analysis typically identifies abnormalities in sperm number, morphology, and motility. Otologic examination and audiologic assessment can identify hearing loss.

Diagnosis/testing.

The diagnosis of CATSPER-related NSMI is established in males by the identification of biallelic pathogenic variants in CATSPER1. The diagnosis of DIS is established in both males and females by the identification of biallelic contiguous gene deletions at chromosome 15q15.3 that includes both CATSPER2 and STRC.

Management.

Treatment of manifestations: For infertile males with DIS or CATSPER-related NSMI, assisted reproductive technologies such as intracytoplasmic sperm injection are likely to be an effective fertility option. For males with DIS, treatment of hearing loss is best achieved by fitting hearing aids for amplification and special educational assistance for school-age children.

Agents/circumstances to avoid: For individuals with DIS, exposure to loud noise.

Evaluation of relatives at risk: For sibs at risk for DIS, audiologic testing in infancy or early childhood to enable early management of hearing loss.

Genetic counseling.

CATSPER-related NSMI and DIS are inherited in an autosomal recessive manner. When both parents are carriers for pathogenic variants, each child has a 25% chance of inheriting both pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither pathogenic variant. Males who inherit two CATSPER1 pathogenic variants will be infertile; females who inherit two CATSPER1 pathogenic variants will have no signs/symptoms. Males who inherit two CATSPER2-STRC deletions will be infertile and deaf; females who inherit two CATSPER2-STRC deletions will be deaf. If the pathogenic variants have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

GeneReview Scope

CATSPER-Related Male Infertility: Included Phenotypes 1
  • CATSPER-related nonsyndromic male infertility (NSMI)
  • Deafness-infertility syndrome (DIS)

For synonyms and outdated names, see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

CATSPER-related male infertility results from abnormalities in sperm and can be either:

  • Nonsyndromic (CATSPER-related nonsyndromic male infertility [NSMI]); or
  • Associated with non-progressive prelingual sensorineural hearing loss (deafness-infertility syndrome [DIS]).

Suggestive Findings

CATSPER-related male infertility should be suspected in individuals with the following clinical features and semen analysis.

Clinical features

  • Male factor infertility
  • Hearing loss in either a male or female:
    • In DIS, prelingual hearing loss in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz)
    • Normal vestibular function

Semen analysis. Routine semen analysis assesses sperm number, morphology, and motility and the function of the genital tract (semen volume and pH) [WHO 1999] (Table 1). Note: Although routine semen analysis effectively identifies azoospermia, changes in sperm morphology and motility can be missed unless the analysis includes measurement of sperm motility (e.g., path velocity, progressive velocity, and track speed).

  • NSMI. While the pH of the semen was in the normal range, examination of all other parameters revealed non-motile sperm or sperm motility below the normal threshold, low sperm count, an increased number of abnormally structured spermatozoa, and reduced semen volume [Avenarius et al 2009].
  • DIS. Semen analysis of males with DIS is normal for sperm count and semen volume, but sperm morphology and motility are abnormal.

Table 1.

Semen Analysis

TestCATSPER-Related Male InfertilityNormal 1
NSMIDIS
Ejaculate volume0.4-1.0 mL1-4 mL1.5-5 mL
pH7.5-8.0Normal>7.2
Sperm concentrationNormaI60-78 million/mL>20 million/mL
Total sperm number (million/ejaculate)10.4-12>40>40
Percent motility (% motile)0%-50%1%-5%>50%
Forward progression (scale 0-4)NormaINormaI>2
Morphology (% normal)20%-65%9%-12%>30%
Sperm agglutination (scale 0-3)NormaINormaI<2
Viscosity (scale 0-4)NormaINormal - 3+<3

NSMI = nonsyndromic male infertility

DIS = deafness-infertility syndrome

1.

Values from ASRM Practice Committee [Male Infertility Best Practice Policy Committee 2006]

Establishing the Diagnosis

Nonsyndromic Male Infertility (NSMI)

The diagnosis of CATSPER-related NSMI is established in males by the identification of biallelic loss-of-function pathogenic variants in CATSPER1 on molecular genetic testing (see Table 2).

Single-gene testing. Sequence analysis of CATSPER1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Alternate testing strategy for NSMI

  • A multi-gene panel that includes CATSPER1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
    For more information on multi-gene panels click here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For more information on comprehensive genomic testing click here.

Deafness-Infertility Syndrome (DIS)

The diagnosis of CATSPER-related DIS is established in both males and females by the identification of biallelic contiguous gene deletions at chromosome 15q15.3 that includes both CATSPER2 and STRC.

Chromosomal microarray (CMA) using oligonucleotide or SNP arrays can detect a contiguous gene deletion involving CATSPER2 and STRC in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 15q15.3 region.

Table 2.

Molecular Genetic Testing Used in CATSPER-Related Male Infertility

Gene 1 or Deletion 2Test MethodProportion of Probands with Pathogenic Variants 3 Detectable by This Method
NSMIDIS
CATSPER1Sequence analysis 42/2 5NA
Gene-targeted deletion/duplication analysis 6Unknown 7NA
Homozygous deletion at 15q15.3 including CATSPER2 and STRCCMA/array CGH 8NA100% 9
UnknownNAUnknown 10Unknown 10

NSMI = nonsyndromic male infertility

DIS = deafness-infertility syndrome

NA = not applicable

1.
2.

See Molecular Genetics for details of the deletion and genes of interest included in the region.

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Two families with homozygous loss-of-function variants in CATSPER1 have been reported [Avenarius et al 2009].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No data on detection rate of gene-targeted deletion/duplication analysis in individuals with NSMI are available.

8.

Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays or array comparative genomic hybridization (array CGH) using fluorescent probesThese approaches are in clinical use targeting the 15q15.3 region. Note: The 15q15.3 deletion may not have been detectable by older oligonucleotide or BAC platforms.

9.

In all cases of CATSPER2-related DIS the entire CATSPER1 gene, as well as STRC, has been deleted as part of a contiguous deletion (see Molecular Genetics). A case of brothers with a heterozygous CATSPER2 deletion and an apparent NSMI phenotype has been reported; however, given the lack of a second pathogenic variant and no evidence of hearing loss, the cause of NSMI in this family was not clear [Jaiswal et al 2014].

10.

The contribution of the other CATSPER gene family members (CATSPER2, CATSPER3, CATSPER4, CATSPERβ, and CATSPERG) to NSMI is unknown [Lobley et al 2003, Liu et al 2007, Cai & Clapham 2008, Wang et al 2009, Hildebrand et al 2010].

Clinical Characteristics

Clinical Description

CATSPER-related male infertility includes CATSPER-related nonsyndromic male infertility (NSMI) and the deafness-infertility syndrome (DIS) [Nikpoor et al 2004, Clapham & Garbers 2005, Benoff et al 2007, Hildebrand et al 2010].

CATSPER-Related Nonsyndromic Male Infertility (NSMI)

CATSPER-related NSMI was reported in two unrelated Iranian families in 2009 [Avenarius et al 2009]. In both families, the affected infertile males were offspring of first-cousin marriages.

Females homozygous for the CATSPER1 pathogenic variant and all heterozygous individuals within a family have normal fertility.

Deafness-Infertility Syndrome (DIS)

Infertility. All males homozygous for CATSPER2-STRC deletion are infertile. Semen analysis is typically abnormal. For example, in one affected male more than 88% of sperm were malformed (mainly thin heads, micro- and irregular acrosomes) and approximately 30% of sperm had short, coiled flagella [Zhang et al 2007]. Following liquidation fewer than 5% of sperm had full swimming capacity. Similar defects were observed in other affected males from the four families [Avidan et al 2003, Zhang et al 2007, Smith et al 2013].

Hearing loss. All affected males and females who are homozygous for the deletion of CATSPER2-STRC have hearing loss, although onset and severity of hearing loss may vary.

  • Typically, the hearing loss in DIS is diagnosed in early childhood. It is non-progressive; vestibular function is normal.
  • In all reported affected males, the degree of hearing loss is moderate to severe across all frequencies (0.25 kHz-8 kHz). This auditory phenotype is comparable to that observed in persons with DFNB16 [Villamar et al 1999, Verpy et al 2001].

Note: Knijnenburg and colleagues reported a male of non-consanguineous parentage with a complex phenotype that included intellectual disability, short stature, dysmorphic features, and hearing loss associated with a homozygous CATSPER2-STRC contiguous gene deletion. Sperm motility could not be assessed in the proband, who was age ten years. The more severe phenotype in this individual may represent one end of a broader phenotypic spectrum associated with homozygous deletion of 15q15.3, or the intellectual disability and dysmorphic features may be unrelated or only partially related to the 15q15.3 deletion [Knijnenburg et al 2009].

Genotype-Phenotype Correlations

Since only two pathogenic loss-of-function variants for CATSPER-related NSMI in two unrelated families have been identified [Avenarius et al 2009], meaningful genotype-phenotype correlations are not possible.

Similarly, all families with DIS have homozygous deletions at 15q15.3 involving loss of CATSPER2 and STRC [Avidan et al 2003, Zhang et al 2007, Knijnenburg et al 2009, Smith et al 2013, Gu et al 2015].

Historical Perspective

DIS was first identified by Avidan and colleagues in a French family segregating deafness, infertility, and congenital dyserythropoietic anemia type 1 (caused by pathogenic variants in CDAN1). The three affected males were homozygous for a p.Asn598Ser missense variant in CDAN1 and were also homozygous for a contiguous gene deletion that involved CATSPER2 and STRC [Avidan et al 2003]. Four years later, three unrelated Iranian families that segregated only deafness and infertility secondary to deletion of CATSPER2 and STRC were identified [Zhang et al 2007]. Zhang and colleagues designated this new syndromic form of hearing loss deafness-infertility syndrome (DIS). None of these families share similar deletions.

Nomenclature

Deafness-infertility syndrome is also known as sensorineural deafness and male infertility.

CATSPER-related nonsyndromic male infertility is also referred to as autosomal recessive nonsyndromic male infertility.

Prevalence

The prevalence of CATSPER-related nonsyndromic male infertility (NSMI) is unknown; only two families have been reported.

The prevalence of deletions at 15q15.3 involving CATSPER2 and STRC was examined in peripheral blood specimens from 5,152 individuals from the general population by array CGH [Hoppman et al 2013]. Of those, 57 individuals (2 of whom were sibs) were found to be heterozygous for similar deletions including CATSPER2 and STRC, indicating that 1.09% of people in this sample were carriers. If this figure is representative of the general population, this would indicate that approximately one in 40,000 individuals is born with a homozygous deletion of this region, resulting in deafness and, in males, infertility [Hoppman et al 2013].

Differential Diagnosis

Male infertility. In approximately half of the 15% of couples who cannot conceive, the cause is ascribed to male infertility as described by Mosher & Pratt [1990] and Templeton et al [1990]. Causes of male infertility other than pathogenic variants in CATSPER are numerous and include but are not limited to the following:

For review of these differential diagnoses refer to Y Chromosome Infertility.

Molecular genetic testing to attempt to identify the involved gene is appropriate. Pathogenic variants in a large number of genes cause male infertility (a partial list includes CATSPER1, AKAP3, AKAP4, DNAH1, DNAH5, DNAH11, SPATA16, PRM1, PRM2, SYCP1, and SYCP3); as asthenospermia (loss or reduction in spermatozoa motility) is caused by pathogenic variants in CATSPER1 (NSMI) [Avenarius et al 2009] and CATSPER2 (DIS) [Avidan et al 2003, Zhang et al 2007], the CATSPER family should be among the first genes tested.

See Spermatogenic failure: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Deafness. See Deafness and Hereditary Hearing Loss Overview.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CATSPER-related male infertility, the following evaluations are recommended (if not performed previously as part of the diagnostic evaluation):

  • In males, pubertal age or older, semen analysis to assess sperm number, motility, and morphology
  • In males and females with DIS, hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Infertility. No available treatment can reverse the morphologic and/or motility defects observed in CATSPER-related asthenospermia or asthenoteratospermia (low motility with increased number of abnormal forms). For infertile males, one option is to bypass these morphologic and motility abnormalities using assisted reproductive technologies such as intracytoplasmic sperm injection (ICSI) [Smith et al 2013]. This approach has been used successfully in males with DIS [Zhang et al 2007].

Deafness. For males and females with DIS, treatment of hearing loss is best achieved by fitting hearing aids for amplification. For school-age children or adolescents, special educational assistance may also be warranted and, where possible, should be offered. (See Deafness and Hereditary Hearing Loss Overview and Related Genetic Counseling Issues for other issues pertinent to the care of deaf and hard-of-hearing persons.)

Prevention of Secondary Complications

Regardless of its etiology, uncorrected hearing loss has consistent sequelae. Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production.

Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention, whether through amplification, otologic surgery, or cochlear implantation, is effective [Smith et al 2005] (see Deafness and Hereditary Hearing Loss Overview).

Although decreased cognitive skills and performance in mathematics and reading are associated with deafness, examination of persons with hereditary hearing loss has shown that these deficiencies are not intrinsically linked to the cause of the deafness.

Thus, early identification and timely intervention are essential for optimal cognitive development in children with prelingual deafness.

Surveillance

Annual monitoring of hearing loss is not required in individuals with DIS because hearing loss is non-progressive.

Agents/Circumstances to Avoid

Individuals with DIS should avoid exposure to loud noise in the workplace or during recreation.

Evaluation of Relatives at Risk

It is appropriate to evaluate the sibs of a proband with DIS in infancy or early childhood in order to identify as early as possible those who would benefit from early support and management of hearing loss. Evaluations can include:

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CATSPER-related nonsyndromic male infertility (NSMI) and deafness-infertility syndrome (DIS) are inherited in an autosomal recessive manner.

Risk to Family Members – CATSPER-Related NSMI

Parents of a proband

  • The parents of a male with CATSPER-related NSMI are typically obligate heterozygotes (i.e., carriers of a pathogenic variant in CATSPER1).
  • Less likely, the mother may have two pathogenic variants and the father has one or, if the pregnancy was conceived using ICSI, the father may be infertile (as a result of having two CATSPER1 pathogenic variants) and the mother has one.
  • Women with two CATSPER1 pathogenic variants and individuals who are heterozygous for CATSPER1 pathogenic variants (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • When both parents are carriers:
    • At conception, each sib of an individual with CATSPER-related NSMI has a 25% chance of inheriting both pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither pathogenic variant.
    • Males who inherit biallelic pathogenic variants will be infertile.
    • Females who inherit biallelic pathogenic variants will have no signs/symptoms.
  • When one parent has two CATSPER1 pathogenic variants and the other parent has one pathogenic variant:
    • Each sib has a 50% chance of inheriting biallelic pathogenic variants (one from each parent) and a 50% chance of inheriting one pathogenic variant.
    • Males who inherit biallelic pathogenic variants will be infertile.
    • Females who inherit biallelic pathogenic variants will have no signs/symptoms.
  • Women with biallelic CATSPER1 pathogenic variants and individuals who have a heterozygous CATSPER1 pathogenic variant (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Assuming that the unaffected parent is not a carrier, the offspring of an individual with CATSPER-related NSMI are obligate heterozygotes (carriers) for a CATSPER1 pathogenic variant.

Other family members of a proband. Each sib of the proband’s parents has a 50% chance of being a carrier of the CATSPER1 pathogenic variant.

Carrier testing of at-risk family members is possible if biallelic CATSPER1 pathogenic variants have been identified in an affected family member.

Risk to Family Members – DIS

Parents of a proband

  • Typically, the parents of a male with DIS are obligate heterozygotes (i.e., carriers of a deletion that includes CATSPER2-STRC).
  • Less likely, the mother may be deaf as a result of being homozygous for the deletion or, if the pregnancy was conceived using ICSI, the father may be deaf and infertile as a result of being homozygous for the deletion. In such cases, the other parent is heterozygous for the CATSPER2-STRC deletion.
  • Heterozygotes (carriers) for the CATSPER2-STRC deletion are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • When both parents are carriers:
    • At conception, each sib of an individual with DIS has a 25% chance of inheriting biallelic CATSPER2-STRC deletions, a 50% chance of inheriting one deletion and being an asymptomatic carrier, and a 25% chance of not inheriting a deletion, having normal hearing and fertility, and not being a carrier.
    • Males who inherit biallelic CATSPER2-STRC deletions will be infertile and deaf.
    • Females who inherit biallelic CATSPER2-STRC deletions will be deaf.
  • When one parent has biallelic CATSPER2-STRC deletions and the other parent is heterozygous for a CATSPER2-STRC deletion:
    • Each sib has a 50% chance of inheriting biallelic deletions (1 from each parent) and a 50% chance of inheriting one deletion.
    • Males who inherit biallelic CATSPER2-STRC deletions will be infertile and deaf.
    • Females who inherit biallelic CATSPER2-STRC deletions will be deaf.

Offspring of a proband. Assuming that the unaffected parent is not a carrier, the offspring of an individual with DIS are obligate heterozygotes (carriers) for the CATSPER2-STRC deletion. (Note: Pregnancies from males with DIS have been achieved using ICSI [Zhang et al 2007].)

Other family members of a proband. Each sib of the proband’s parents has at least a 50% chance of being a carrier of the CATSPER2-STRC deletion.

Carrier testing of at-risk family members is possible if biallelic CATSPER2-STRC deletions have been identified in an affected family member.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

The following points regarding hearing loss/deafness are noteworthy:

  • Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
  • Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a “treatment” or “cure,” or to be “prevented.”
  • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.
  • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as “abnormal” should be avoided.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are infertile or deaf.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CATSPER-related male infertility are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • InterNational Council on Infertility Information Dissemination, Inc. (INCIID)
    5765 F Burke Centre Pkwy
    Box 330
    Burke VA 22015
    Email: inciidinfo@inciid.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • RESOLVE: The National Infertility Association
    7918 Jones Branch Drive
    Suite 300
    McLean VA 22102
    Phone: 703-556-7172
    Fax: 703-506-3266
    Email: info@resolve.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CATSPER-Related Male Infertility: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CATSPER-Related Male Infertility (View All in OMIM)

606389CATION CHANNEL, SPERM-ASSOCIATED, 1; CATSPER1
606440STEREOCILIN; STRC
607249CATION CHANNEL, SPERM-ASSOCIATED, 2; CATSPER2
611102DEAFNESS-INFERTILITY SYNDROME; DIS
612997SPERMATOGENIC FAILURE 7; SPGF7

Molecular Genetic Pathogenesis

NSMI. Despite the fact that a significant number of genes are implicated in NSMI [Matzuk & Lamb 2008], the genetic etiology often goes undiagnosed in the absence of more rigorous characterization of the sperm phenotype that includes measurement of sperm motility parameters such as path velocity, progressive velocity, and track speed. Pathogenic variants in CATSPER1 cause an inherited form of NSMI.

DIS. DIS is a specific syndrome that results from homozygous CATSPER2-STRC deletion. CATSPER1 and CATSPER2 are members of the same gene family.

CATSPER1

Gene structure. CATSPER1 has a transcript length of 2,634 base pairs (bp) with 12 exons (NM_053054.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The pathogenic variants in Table 3 are the only two reported for CATSPER1 to date [reviewed in Hildebrand et al 2010]. These frameshifts in exon 1, identified in two Iranian families, are predicted to result in premature stop codons and complete loss of CATSPER1 protein as a result of nonsense-mediated decay (NMD) or truncated proteins lacking all transmembrane domains and the channel pore.

Based on these data, loss-of-function variants of CATSPER1 are predicted to result in NSMI, although no additional variants have been associated with disease [Avenarius et al 2009]. It is not known whether less disruptive gene alterations (e.g., missense variants) also lead to NSMI.

Table 3.

Selected CATSPER1 Pathogenic Variants Associated with NSMI

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.539dupT 2p.His182ProfsTer8NM_053054​.3
NP_444282​.3
c.944_948dupATGGC
(948-949insATGGC) 2
p.Asp317MetfsTer20

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Normal gene product. CATSPER1 protein is a 780-amino acid calcium channel that most closely resembles a single six-transmembrane-spanning repeat of the voltage-dependent calcium channel four-repeat structure. CATSPER is vital to cAMP-mediated calcium influx, sperm motility, and fertilization [Ren et al 2001].

Abnormal gene product. Loss of CATSPER1 function is associated with disease. Sperm motility parameters are all markedly impaired in CatSper1-/- (knockout) mouse sperm as compared to wild-type sperm [Ren et al 2001].

CATSPER2

Gene structure. CATSPER2 comprises 13 exons and has a transcript length of 1948 bp (NM_172095.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 4. In all cases of DIS (1 French and 3 Iranian) resulting from homozygous CATSPER2-STRC deletion, the entire CATSPER2 gene is deleted [Avidan et al 2003, Zhang et al 2007, reviewed in Hildebrand et al 2010].

It is unclear whether nonsense or missense variants in CATSPER2 would lead to a NSMI phenotype.

Table 4.

Selected CATSPER2/STRC Pathogenic Variants Associated with DIS

Chromosome RearrangementGenes DeletedReference Sequences
Del(15)(q15.1-q15.3) 1CATSPER2 and STRCCATSPER2 isoform 1: STRC:

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature

1.

Normal gene product. CATSPER2 protein is 530 amino acids in length. It is one of several sperm-specific voltage-gated ion channels that have a Ca2+ ion-selective pore domain that is required for sperm cell motility and activated by progesterone signaling [Quill et al 2001, Qi et al 2007, Smith et al 2013].

Abnormal gene product. Reported pathogenic variants in CATSPER2 are deletion of the entire gene as part of a contiguous gene deletion syndrome [Avidan et al 2003]. The deletion is predicted to result in complete absence of CATSPER2 protein.

Deletion of CATSPER2 is the cause of infertility in males with DIS based on murine data showing that independent loss of CATSPER2 protein in sperm leads to infertility in males [Ren et al 2001, Qi et al 2007, Avenarius et al 2009].

STRC

Gene structure. STRC is a 29-exon gene and has a transcript length of 5,515 bp (NM_153700.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The only known pathogenic variants of STRC in individuals with DIS are contiguous deletions that also delete CATSPER2 [Avidan et al 2003, Zhang et al 2007] (see Table 4). Other pathogenic variants in STRC as associated with nonsyndromic hearing loss (see Deafness and Hereditary Hearing Loss Overview.)

Normal gene product. STRC protein is 1775 amino acids in length (NP_714544.1). It is expressed in the stereocilia hair-bundle of outer hair cells, the inner ear cells that amplify the initial stimulation [Verpy et al 2008]. A deletion of the contiguous genes CATSPER2 and STRC results in the DIS phenotype; intragenic variants in STRC result in autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB16 locus [Verpy et al 2001, Avidan et al 2003, Zhang et al 2007, Knijnenburg et al 2009].

Abnormal gene product. Reported pathogenic variants in STRC that cause DIS are homozygous deletions of the entire gene as part of contiguous gene deletion that includes CATSPER2; deletion of STRC results in loss of its encoded protein, stereocilin.

Deletion of STRC, which encodes stereocilin, underlies the hearing loss in DIS. Pathogenic variants of only STRC result in ARNSHL at the DFNB16 locus [Verpy et al 2001]. This is supported by the generation of Strc-/- (knockout) mice that have a specific outer hair cell defect, while their inner hair cells appear unaffected [Verpy et al 2001]. Inactivation of Strc in mice leads to failure of the cochlear amplifier [Verpy et al 2008]. This murine phenotype is in agreement with the moderate-to-severe hearing loss usually observed in individuals with DFNB16 or DIS.

References

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Suggested Reading

  • Carlson AE, Burnett LA, del Camino D, Quill TA, Hille B, Chong JA, Moran MM, Babcock DF. Pharmacological targeting of native CatSper channels reveals a required role in maintenance of sperm hyperactivation. PLoS One. 2009;4:e6844. [PMC free article: PMC2729922] [PubMed: 19718436]
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Chapter Notes

Acknowledgments

RJHS is the Sterba Hearing Research Professor, University of Iowa College of Medicine and is supported by NIH NIDCD grants RO1DC00354 and RO1 DC002842. MSH is supported by an Australian National Health and Medical Research (NHMRC) Overseas Biomedical Postdoctoral Training Fellowship.

Revision History

  • 23 March 2017 (ma) Comprehensive update posted live
  • 7 August 2014 (me) Comprehensive update posted live
  • 9 August 2012 (me) Comprehensive update posted live
  • 3 December 2009 (me) Review posted live
  • 13 August 2009 (rjhs) Initial submission
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