CATSPER-Related Male Infertility – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Michael S Hildebrand, PhD, Matthew R Avenarius, PhD, and Richard JH Smith, MD.
Author Information and AffiliationsInitial Posting: December 3, 2009; Last Update: March 23, 2017.
Estimated reading time: 23 minutes
Summary
NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.
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.
Diagnosis
CATSPER-related male infertility results from abnormalities in sperm and can be either:
Suggestive Findings
CATSPER-related male infertility should be suspected in individuals with the following clinical features and semen analysis.
Clinical features
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).
Table 1.
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| Test | CATSPER-Related Male Infertility | Normal 1 |
|---|
| NSMI | DIS |
|---|
|
Ejaculate volume
| 0.4-1.0 mL | 1-4 mL | 1.5-5 mL |
|
pH
| 7.5-8.0 | Normal | >7.2 |
|
Sperm concentration
| Normal | 60-78 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) | Normal | Normal | >2 |
| Morphology (% normal) | 20%-65% | 9%-12% | >30% |
| Sperm agglutination (scale 0-3) | Normal | Normal | <2 |
| Viscosity (scale 0-4) | Normal | Normal – 3+ | <3 |
DIS = deafness-infertility syndrome; NSMI = nonsyndromic male infertility
- 1.
Establishing the Diagnosis
Nonsyndromic Male Infertility (NSMI)
The diagnosis of CATSPER-related NSMI is established in males by identification of biallelic loss-of-function pathogenic (or likely pathogenic) variants in CATSPER1 on molecular genetic testing (see Table 2).
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic CATSPER1 variants of uncertain significance (or of one known CATSPER1 pathogenic variant and one CATSPER1 variant of uncertain significance) does not establish or rule out the diagnosis.
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
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
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| Gene 1 or Deletion 2 | Method | Proportion of Probands with Pathogenic Variants 3 Detectable by Method |
|---|
| NSMI | DIS |
|---|
|
CATSPER1
| Sequence analysis 4 | 2/2 5 | NA |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 | NA |
| Homozygous deletion at 15q15.3 including CATSPER2 and STRC | CMA/array CGH 8 | NA | 100% 9 |
| Unknown | NA | Unknown 10 | Unknown 10 |
DIS = deafness-infertility syndrome; NA = not applicable; NSMI = nonsyndromic male infertility
- 1.
- 2.
See Molecular Genetics for details of the deletion and genes of interest included in the region.
- 3.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; 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 used may include a range of techniques such as 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.
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].
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.
Note: Knijnenburg and colleagues reported a male of nonconsanguineous 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].
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:
Obstruction of the ejaculatory ducts (e.g.,
cystic fibrosis and congenital absence of the vas deferens)
Immunologic abnormalities (e.g., anti-sperm antibodies)
Infection (e.g., mumps orchitis, epididymitis, urethritis)
Vascular abnormalities (e.g., varicocele)
Trauma
Testicular tumor
Exposure to toxic agents (e.g., radiation, chemotherapy agents, heat)
Klinefelter syndrome (47,XXY)
Balanced chromosome rearrangements
Sertoli-cell-only syndrome
For review of these differential diagnoses refer to Y Chromosome Infertility: Differential Diagnosis.
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 OMIM Phenotypic Series: Spermatogenic failure to view genes associated with this phenotype in OMIM.
Deafness. See Genetic 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 Genetic 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 Genetic 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 in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise 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.
DIS – Risk to Family Members
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
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 detection. Carrier testing of at-risk family members is possible if biallelic CATSPER2-STRC deletions have been identified in an affected family member.
Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CATSPER-related male infertility are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
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)
Phone: 703-379-9178
Fax: 703-379-1593
Email: INCIIDinfo@inciid.org
National Association of the Deaf
Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
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
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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.
Molecular 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
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DNA Nucleotide Change
(Alias 1) | Predicted Protein Change | Reference Sequences |
|---|
| c.539dupT 2 | p.His182ProfsTer8 |
NM_053054.3
NP_444282.3
|
c.944_948dupATGGC
(948-949insATGGC) 2 | p.Asp317MetfsTer20 |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
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
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
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 Genetic 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.
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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