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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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CATSPER-Related Male Infertility

, PhD, , PhD, and , MD.

Author Information
, PhD
Epilepsy Research Centre
Department of Medicine
University of Melbourne
Melbourne, Australia
, PhD
Oregon Hearing Research Center
Oregon Health and Science University
Portland, Oregon
, MD
Department of Otolaryngology, Head & Neck Surgery
University of Iowa
Iowa City, Iowa

Initial Posting: ; Last Update: August 9, 2012.

Summary

Disease 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.

Diagnosis/testing. Routine semen analysis can identify abnormalities in sperm number, morphology, and motility. Otologic examination and audiologic assessment can identify the hearing loss. CATSPER-related NSMI is caused by mutations in CATSPER1; DIS is caused by a contiguous gene deletion at chromosome 15q15.3 including CATSPER2 and STRC. The diagnosis of either NSMI or DIS can be made only by molecular genetic testing.

Management. Treatment of manifestations: For infertile males with DIS, assisted reproductive technologies (ARTs) such as intracytoplasmic sperm injection (ICSI) are an option. Its use in males with CATSPER1-related NSMI has not been reported. 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.

Surveillance: Not indicated since infertility and hearing loss are stable.

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 disease-causing mutations, each child has a 25% chance of inheriting both mutations, a 50% chance of inheriting one mutation and being an asymptomatic carrier, and a 25% chance of inheriting neither mutation. Males who inherit two CATSPER1 mutations will be infertile; females who inherit two CATSPER1 mutations 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 causative mutations 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 Disorders
  • CATSPER-related nonsyndromic male infertility
  • Deafness-infertility syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical 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])

The diagnosis of either NSMI or DIS can be made only by molecular genetic testing.

Testing

Sperm 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. Clinical analysis of semen from affected males in both families showed sperm defects and reduced fertility. The analysis included measurement of volume, pH, sperm count, sperm motility, and sperm form (structure). 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. For example, in one patient 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 affected males from the other three families [Avidan et al 2003, Zhang et al 2007].

Table 1. Semen Analysis

TestCATSPER-Related Male InfertilityNormal 1
NSMIDIS
Ejaculate volume 0.4-1.0 mL1-4 mL1.5-5 mL
pH7.5-8.0 Normal>7.2
Sperm concentration NormaI60-78 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]

Hearing evaluation including otologic examination and audiologic assessment (including measurement of bone conduction) should be completed. In DIS the hearing loss is prelingual in the moderate-to-severe range across all frequencies (0.25 kHz – 8 kHz). Vestibular function is normal.

Molecular Genetic Testing

Genes

  • CATSPER1 mutations are associated with NSMI (CATSPER-related nonsyndromic male infertility).
  • A contiguous gene deletion at chromosome 15q15.3 including CATSPER2 and STRC is associated with DIS (deafness-infertility syndrome).

Evidence for locus heterogeneity. 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].

Table 2. Summary of Molecular Genetic Testing Used in CATSPER-Related Male Infertility

Gene 1Proportion of CATSPER-Related NSMI and DIS Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
CATSPER1Unknown for NSMISequence analysis See Table 3
CATSPER2 and STRC 4100% for DISDeletion/ duplication analysis 5Contiguous gene deletion 4; see Table 4

NSMI = nonsyndromic male infertility

DIS = deafness-infertility syndrome

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. The contribution of the other CATSPER gene family members (CATSPER2, CATSPER3, CATSPER4, CATSPERB, and CATSPERG) to NSMI is unknown.

3. See Molecular Genetics for information on allelic variants.

4. In all cases of DIS caused by mutation in CATSPER2, the entire CATSPER2 gene has been deleted as part of a contiguous gene deletion that also includes STRC (see Molecular Genetics).

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To establish the diagnosis in a proband

1.

Clinical evaluation (physical examination, semen analysis, audiology)

2.

Molecular genetic testing

  • Sequence analysis of CATSPER1 for males with NSMI
  • Deletion/duplication analysis for males with DIS

Carrier testing for at-risk relatives requires prior identification of the causative mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the causative mutations in the family.

Clinical Description

Natural History

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 caused by mutations in CATSPER1 was first 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 mutation and all heterozygous individuals within a family have normal fertility.

Deafness-infertility syndrome (DIS). DIS was first identified by Avidan and colleagues in a French family segregating deafness, infertility, and congenital dyserythropoietic anemia type 1 (caused by mutation of CDAN1). The three affected males were homozygous for a p.Asn598Ser missense mutation 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 as deafness-infertility syndrome (DIS). None of these families share similar deletions.

All males homozygous for CATSPER2-STRC deletion are infertile. The penetrance for the hearing loss in affected males and females who are homozygous for the deletion of CATSPER2-STRC in DIS is 100% although onset and severity of hearing loss may vary.

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. Because the proband was only ten years old, sperm motility could not be assessed. 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].

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 [Verpy et al 2001, Villamar et al 1999].

Genotype-Phenotype Correlations

Since only a few mutations/deletions for CATSPER-related NSMI (n=2) and DIS (n=4) have been identified, meaningful genotype-phenotype correlations are not possible.

Penetrance

The penetrance of NSMI caused by mutations in CATSPER1 is complete in males homozygous for a nonsense mutation [Avenarius et al 2009]. Females homozygous for the mutation and all heterozygous individuals have normal fertility.

In males with DIS, the penetrance of the hearing loss and infertility is 100%; all affected females also have hearing loss, although they are not infertile.

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) and deafness-infertility syndrome (DIS) is unknown.

Differential Diagnosis

See Spermatogenic Failure: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

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 CATSPER mutation are numerous and include but are not limited to:

  • Obstruction of the ejaculatory ducts (e.g., cystic fibrosis [CF] and congenital bilateral absence of the vas deferens [CBAVD]) (see CFTR-Related Disorders)
  • Abnormal sperm motility (see Primary Ciliary Dyskinesia)
  • Immunologic abnormalities (e.g., anti-sperm antibodies)
  • Infection (e.g., mumps orchitis, epididymitis, urethritis)
  • Vascular abnormalities (e.g., varicocele)
  • Trauma
  • Endocrine abnormalities (e.g., congenital adrenal hyperplasia [see 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia], isolated follicle-stimulating hormone [FSH] deficiency, hyperprolactinemia)
  • Testicular tumor
  • Exposure to toxic agents (e.g., radiation, chemotherapy agents, heat)
  • Klinefelter syndrome (XXY)
  • Balanced chromosome rearrangements
  • Sertoli-cell-only syndrome (SCOS)

For review of these differential diagnoses refer to Y Chromosome Infertility [Silber & Disteche 2012].

Molecular genetic testing to attempt to identify the involved gene is appropriate. Mutations 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 mutations 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.

Deafness. See Deafness and Hereditary Hearing Loss Overview.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

The extent of disease in a male diagnosed with CATSPER-related infertility can be determined by:

  • Semen analysis to assess sperm number, motility, and morphology
  • Audiologic evaluation
  • Medical genetics consultation

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, an option to conception is to bypass these morphologic and motility abnormalities using assisted reproductive technologies (ARTs) like intracytoplasmic sperm injection (ICSI). This approach has been successfully used in males with DIS [Zhang et al 2007]. Its use in males with CATSPER1-related NSMI has not been reported.

Deafness. For males 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 Related Genetic Counseling Issues for other issues pertinent to the care of deaf and hard-of-hearing persons.)

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

In DIS, molecular genetic testing in infancy or early childhood can determine whether an at-risk child has inherited the causative contiguous gene deletion; early support and management can then be provided.

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

Therapies Under Investigation

Search Clinical Trials.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 NSMI and DIS are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

CATSPER1-related nonsyndromic male infertility

  • The parents of a male with CATSPER1-related NSMI are typically obligate heterozygotes for the mutation in CATSPER1.
  • Less likely, the mother may have two mutations 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 mutations and the mother has one.
  • Women with two CATSPER1 mutations and individuals who are heterozygous for CATSPER1 mutations (carriers) are asymptomatic.

Deafness-infertility syndrome (DIS)

  • Typically, the parents of a male with DIS are obligate heterozygotes for 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) of the CATSPER2-STRC deletion are asymptomatic.

Sibs of a proband

CATSPER1-related nonsyndromic male infertility

When both parents are carriers:

  • At conception, each sib of an individual with CATSPER1-related NSMI has a 25% chance of inheriting both mutations, a 50% chance of inheriting one mutation and being an asymptomatic carrier, and a 25% chance of inheriting neither mutation, having normal hearing and fertility, nor being a carrier.
    • Males who inherit two mutations will be infertile.
    • Females who inherit two mutations will have no signs/symptoms.
  • Once an at-risk male sib is known to have normal fertility, the chance of being a carrier of the CATSPER1 mutation is 2/3.
  • Determination of carrier status of at-risk female sibs requires molecular genetic testing.

When one parent has two CATSPER1 mutations and the other parent has one mutation:

  • Each sib has a 50% chance of inheriting both mutations and a 50% chance of inheriting one mutation.
    • Males who inherit two mutations will be infertile.
    • Females who inherit two mutations will have no signs/symptoms.

Women with two CATSPER1 mutations and individuals who are heterozygous for CATSPER1 mutations (carriers) are asymptomatic.

Deafness-infertility syndrome (DIS)

When both parents are carriers:

  • At conception, each sib of an individual with DIS has a 25% chance of inheriting two 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 two CATSPER2-STRC deletions will be infertile and deaf.
    • Females who inherit two CATSPER2-STRC deletions will be deaf.
  • Once an at-risk male sib is known to have normal fertility and/or hearing, the chance of being a carrier of the CATSPER2-STRC deletions is 2/3.
  • Once an at-risk female sib is known to have normal hearing, the chance of being a carrier of the CATSPER2-STRC deletions is 2/3.

When one parent has two CATSPER2-STRC deletions and the other parent has one CATSPER2-STRC deletion:

  • Each sib has a 50% chance of inheriting one deletion from each parent and a 50% chance of inheriting one deletion.
    • Males who inherit two CATSPER2-STRC deletions will be infertile and deaf.
    • Females who inherit two CATSPER2-STRC deletions will be deaf.

Offspring of a proband

  • Pregnancies from males with DIS have been achieved using ICSI [Zhang et al 2007].
  • The offspring of an individual with CATSPER-related NSMI or DIS are obligate heterozygotes (carriers) for a CATSPER1 mutation or the CATSPER2-STRC deletion, depending on the genetic status of the other (unaffected) parent.

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 CATSPER1 mutation or the CATSPER2-STRC deletion, depending on the genetic status of the proband.

Carrier Testing

Carrier testing of at-risk family members is possible if the causative mutations in the family have been identified.

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 are noteworthy:

  • Communication with profoundly deaf persons may require the services of a skilled interpreter.
  • Deaf persons who are part of the Deaf (capital “D”) community often 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 persons 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. As in all genetic counseling, it is important for the counselor to identify, acknowledge and respect the individual's/family's questions, concerns and fears.
  • The use of certain terms is preferred: probability or chance vs. risk; deaf and hard-of-hearing vs. hearing impaired. Terms such as "affected," "abnormal," and "disease-causing" 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

If the causative mutations 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.

Requests for prenatal testing for conditions such as deafness are not common. 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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which both CATSPER1-related NSMI-causing mutations or the CATSPER2-STRC deletion causing DIS have been identified.

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)
    PO Box 6836
    Arlington VA 22206
    Phone: 703-379-9178
    Fax: 703-379-1593
    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
    1760 Old Meadow Road
    Suite 500
    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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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, SENSORINEURAL, AND MALE INFERTILITY
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 like path velocity, progressive velocity, and track speed. These parameters are all markedly impaired in CatSper1-/- (knockout) mouse sperm as compared to wild-type sperm [Ren et al 2001].

DIS. 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]. Deletion of STRC, which encodes stereocilin, underlies the hearing loss in DIS. Mutations of only STRC result in autosomal recessive nonsyndromic hearing loss (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 mouse 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.

CATSPER1

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

Pathogenic allelic variants. The two known pathogenic variants are located in exon 1 of CATSPER1. This exon encodes a domain of unknown function. Both alleles are insertion mutations leading to a frameshift and a premature stop codon. See Table 3. Based on this data nonsense mutations of CATSPER1 are predicted to result in NSMI, although none have been reported to date [Avenarius et al 2009]. The mutations in Table 3 are the only two reported for CATSPER1 to date [reviewed in Hildebrand et al 2010]. It is not known whether less disruptive gene alterations (e.g., missense mutations) also lead to NSMI.

Table 3. Selected CATSPER1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference SequencesEthnicity of FamilyPhenotype
c.539dupT 2p.His182ProfsTer8
(Lys180LysfsTer8)
NM_053054​.3 NP_444282​.3IranianNSMI
c.944_948dup
(948-949insATGGC) 2
p.Asp317MetfsTer20IranianNSMI

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Avenarius et al [2009]

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. Reported mutations in CATSPER1 are insertion mutations in exon 1 that lead to frameshift and premature stop codons. These changes are predicted to lead to complete loss of CATSPER1 protein as a result of nonsense-mediated decay (NMD) or truncated proteins lacking all transmembrane domains and the channel pore.

CATSPER2

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

Pathogenic allelic variants. See Table 4. In all cases of DIS 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 mutations in CATSPER2 would lead to a NSMI phenotype.

Table 4. Selected CATSPER2/STRC Pathogenic Variants

Chromosome RearrangementGenes Deleted Reference SequencesEthnicity of FamilyPhenotype
Del(15)(q15.1-q15.3) 1CATSPER2 and STRCCATSPER2 isoform 1:
NM_172095​.1 NP_742093​.1

STRC:
NM_153700​.2
NP_714544​.1
French (n=1)
Iranian (n=3)
DIS

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature

1. Avidan et al [2003], Zhang et al [2007]

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

Abnormal gene product. Reported mutations 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.

STRC

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

Pathogenic allelic variants. The only known pathogenic allelic 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).

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 result in the DIS phenotype; intragenic mutation in STRC results in autosomal recessive nonsyndromic hearing loss at the DFNB16 locus [Verpy et al 2001, Avidan et al 2003, Zhang et al 2007, Knijnenburg et al 2009].

Abnormal gene product. Reported mutations 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.

References

Literature Cited

  1. Avenarius MR, Hildebrand MS, Zhang Y, Meyer NC, Smith LL, Kahrizi K, Najmabadi H, Smith RJ. Human male infertility caused by mutations in the CATSPER1 channel protein. Am J Hum Genet. 2009;84:505–10. [PMC free article: PMC2667975] [PubMed: 19344877]
  2. Avidan N, Tamary H, Dgany O, Cattan D, Pariente A, Thulliez M, Borot N, Moati L, Barthelme A, Shalmon L, Krasnov T, Ben-Asher E, Olender T, Khen M, Yaniv I, Zaizov R, Shalev H, Delaunay J, Fellous M, Lancet D, Beckmann JS. CATSPER2, a human autosomal nonsyndromic male infertility gene. Eur J Hum Genet. 2003;11:497–502. [PubMed: 12825070]
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Suggested Reading

  1. 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]
  2. Costello S, Michelangeli F, Nash K, Lefievre L, Morris J, Machado-Oliveira G, Barratt C, Kirkman-Brown J, Publicover S. Ca2+-stores in sperm: their identities and functions. Reproduction. 2009;138:425–37. [PMC free article: PMC3552241] [PubMed: 19542252]
  3. Ho K, Wolff CA, Suarez SS. CatSper-null mutant spermatozoa are unable to ascend beyond the oviductal reservoir. Reprod Fertil Dev. 2009;21:345–50. [PubMed: 19210926]
  4. Wang H, Liu J, Cho KH, Ren D. A novel, single, transmembrane protein CATSPERG is associated with CATSPER1 channel protein. Biol Reprod. 2009;81:539–44. [PMC free article: PMC2731986] [PubMed: 19516020]
  5. Xia J, Ren D. The BSA-induced Ca(2+) influx during sperm capacitation is CATSPER channel-dependent. Reprod Biol Endocrinol. 2009;7:119. [PMC free article: PMC2775032] [PubMed: 19860887]
  6. Xia J, Ren D. Egg coat proteins activate calcium entry into mouse sperm via CATSPER channels. Biol Reprod. 2009;80:1092–8. [PMC free article: PMC2804799] [PubMed: 19211808]

Chapter Notes

Author Notes

Molecular Otolaryngology Research Laboratories (MORL) Homepage: www.healthcare.uiowa.edu/labs/morl

Hereditary Hearing Loss Homepage: hereditaryhearingloss.org

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

  • 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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