Alternative titles; symbols
HGNC Approved Gene Symbol: DZIP1
Cytogenetic location: 13q32.1 Genomic coordinates (GRCh38): 13:95,578,202-95,644,706 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q32.1 | ?Mitral valve prolapse 3 | 610840 | Autosomal dominant | 3 |
| Spermatogenic failure 47 | 619102 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned DZIP1, which they designated KIAA0996. The transcript contains repetitive elements in both the 5-prime and 3-prime UTRs, and the deduced 848-amino acid protein shares weak homology with the mouse hyaluronan-mediated motility receptor (600936). RT-PCR ELISA detected ubiquitous expression, with highest levels in brain, kidney, ovary, testis, lung, pancreas, spinal cord, and all adult brain regions examined. Lower expression was detected in heart, liver, skeletal muscle, spleen, and fetal brain and liver.
Using DAZ (400003) as bait in a yeast 2-hybrid screen of a testis cDNA library, Moore et al. (2004) cloned 2 splice variants of DZIP1, which they called DZIPt1 and DZIPt2. They referred to the DZIP1 variant cloned from brain by Nagase et al. (1999) as DZIPb. All 3 variants encode proteins with a C2H2-type zinc finger domain. The deduced DZIPt1 and DZIPt2 proteins contain 277 and 867 amino acids, respectively. DZIPt2 has a calculated molecular mass of 98 kD. Northern blot analysis detected transcripts of about 1.35, 2.4, 3.9, and 4.4 kb in testis. Expression of DZIP1 was highest in testis, with much lower expression in skeletal muscle and ovary. Quantitative PCR detected DZIP1 in fetal brain, ovary, and testis, and also in adult oocytes and testis. DZIP1 was also expressed in undifferentiated embryonic stem cells. Expression of DZIPt1 was not detected in testis of men with Sertoli cell-only syndrome (400042), which lack germ cells. Western blot analysis of human testis detected DZIP1 proteins of about 100 and 113 kD. Immunohistochemical analysis of fetal testis sections localized DZIP1 to the nucleus and cytoplasm of primordial germ cells, where it colocalized with DAZ and DAZL (601486). In adult testis, DZIP1 localized to the nucleus of spermatogonia, with some cytoplasmic staining. DZIP1 protein was not detected in primary spermatocytes, but it was detected in more mature germ cells, where it was predominantly nuclear. A similar staining pattern was found in mouse embryonic stem cells and adult testis.
By genomic sequence analysis, Christian et al. (2002) mapped the DZIP1 gene to chromosome 13q32-q33. Moore et al. (2004) mapped the DZIP1 gene to chromosome 13q31.
By coimmunoprecipitation assays, Moore et al. (2004) determined that DAZ can form stable complexes with DZIPt1 or DZIPt2. Domain analysis indicated that the C2H2 zinc finger region of DZIPt1 may interact with more than 1 region of DAZ.
Mitral Valve Prolapse 3
In a large 4-generation family with mitral valve prolapse mapping to chromosome 13q31.3-q32.1 (MVP3; 610840), Toomer et al. (2019) identified heterozygosity for a missense mutation in the DZIP1 gene (608671.0001) that segregated fully with disease. The authors designated the change S24R or S70R, respectively, in the 2 known DZIP1 isoforms. Based on this family as well as their analyses of human mitral valve leaflets and a mouse model, Toomer et al. (2019) concluded that cilia defects can cause myxomatous mitral valve disease in humans.
Spermatogenic Failure 47
In 2 unrelated Han Chinese men with infertility due to absent or short sperm flagella (SPGF47; 619102), Lv et al. (2020) identified homozygosity for mutations in the DZIP1 gene: a nonsense mutation (Y230X; 608671.0002) and a missense mutation (R63Q; 608671.0003), respectively.
Mitral Valve Prolapse
Using CRISPR-Cas9, Toomer et al. (2019) generated mice with an S14R mutation in the Dzip1 gene, corresponding to the S24R DZIP1 human mutation (see MOLECULAR GENETICS). Adult mice heterozygous for the S14R variant developed myxomatous mitral valves and functional mitral valve prolapse (MVP). Histologic analysis at birth revealed that all heterozygous mice exhibited a mitral valve phenotype of variable severity, which correlated with a reduction in cilia length. Gene ontology analyses at embryonic day (E) 13.5 demonstrated that the most significant changes in mutant hearts compared to controls were those associated with the extracellular matrix (ECM) pathways; the authors suggested that these changes in ECM composition at E13.5 likely represent early changes in the molecular profile of the developing heart. Genetic removal of Dzip1 from valve mesenchyme progenitor cells resulted in a reduction in primary cilia length during development and concomitant anatomic changes in the mitral valves, similar to those seen in the S14R mutant mice. Mitral valves of Dzip1 conditional knockout mice showed a myxomatous phenotype with increased proteoglycans and collagen and loss of the normal ECM zonal boundaries compared to control mitral leaflets. Functional echocardiography revealed prolapse and leaflet elongation in the Dzip1-deficient mice; MVP was never observed in the control mice. The authors concluded that rare damaging DZIP1 mutations can cause MVP by altering ciliogenic programs during development.
Spermatogenic Failure
Lv et al. (2020) generated Dzip1-knockout male mice, which were all infertile. Few spermatozoa were collected from the epididymides of the mutant mice, and no motile spermatozoa were seen. Light microscopy of the mutant spermatozoa showed severe morphologic abnormalities, primarily absent flagella as well as residual cytoplasm and abnormal heads.
In 15 affected members over 3 generations of a family with mitral valve prolapse (MVP3; 610840), Toomer et al. (2019) identified heterozygosity for a G-to-T transversion (chr13.96,294,074G-T, GRCh37) in exon 5 of the DZIP1 gene, resulting in a substitution at a highly conserved serine residue. The authors designated the change as ser24-to-arg (S24R) or ser70-to-arg (S70R), respectively, in the 2 known DZIP1 isoforms. The mutation segregated fully with disease in the family, and was not found in the dbSNP database; however, it was present at low minor allele frequency (1.081 x 10(-5)) in the gnomAD database. Quantitative analysis showed that the mutant has a significantly reduced half-life compared to wildtype DZIP1. The authors generated mice heterozygous for an S14R mutation in the Dzip1 gene, corresponding to the S24R mutation in human DZIP1, and observed that adult mice developed myxomatous mitral valves and functional mitral valve prolapse.
In a 28-year-old Han Chinese man (family A033) with infertility due to absent or short sperm flagella (SPGF47; 619102), Lv et al. (2020) identified homozygosity for a c.690T-G transversion (c.690T-G, ENST00000376829.2) in exon 7 of the DZIP1 gene, resulting in a tyr230to-ter (Y230X) substitution in the first coiled-coil domain. The proband's first-cousin parents were heterozygous for the mutation, which was not found in 300 fertile Han Chinese individuals, 668 infertile men without morphologic abnormalities of the sperm flagella, or in the 1000 Genomes Project, ExAC, or gnomAD databases. Western blot of transfected HEK293T cells confirmed the presence of the shorter and more mobile truncated protein compared to wildtype DZIP1. Immunofluorescence staining of patient sperm showed no organized axoneme and complete absence of DZIP1, with IFT88 (600595) and IFT140 (614620) weakly staining or misplaced in the sperm head and absent in the sperm tail. Staining for the centriolar protein Centrin1 (CETN1; 603187) revealed an abnormal angle of the 2 centriolar dots, no concentrated dot, or more than 2 centriolar dots. None of the mutant spermatozoa had well-shaped axonemes, and more than half had abnormal numbers of centrioles, a significant increase compared to control sperm.
In a 27-year-old Han Chinese man (family A029) with infertility due to absent or short sperm flagella (SPGF47; 619102), Lv et al. (2020) identified homozygosity for a c.188G-A transition (c.188G-A, ENST00000376829.2) in exon 5 of the DZIP1 gene, resulting in an arg63-to-gln (R63Q) substitution at a highly conserved residue. Familial segregation was not reported, but the mutation was not found in 300 fertile Han Chinese individuals, 668 infertile men without morphologic abnormalities of the sperm flagella, or in the 1000 Genomes Project, ExAC, or gnomAD databases. Western blot of transfected HEK293T cells showed markedly reduced expression of the R63Q mutant compared to wildtype DZIP1. Immunofluorescence staining of patient sperm showed no organized axoneme and complete absence of DZIP1, with IFT88 (600595) and IFT140 (614620) weakly staining or misplaced in the sperm head and absent in the sperm tail.
Christian, S. L., McDonough, J., Liu, C., Shaikh, S., Vlamakis, V., Badner, J. A., Chakravarti, A., Gershon, E. S. An evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia. Genomics 79: 635-656, 2002. [PubMed: 11991713] [Full Text: https://doi.org/10.1006/geno.2002.6765]
Lv, M., Liu, W., Chi, W., Ni, X., Wang, J., Cheng, H., Li, W.-Y., Yang, S., Wu, H., Zhang, J., Gao, Y., Liu, C., and 19 others. Homozygous mutations in DZIP1 can induce asthenoteratospermia with severe MMAF. J. Med. Genet. 57: 445-453, 2020. [PubMed: 32051257] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106479]
Moore, F. L., Jaruzelska, J., Dorfman, D. M., Reijo-Pera, R. A. Identification of a novel gene, DZIP (DAZ-interacting protein), that encodes a protein that interacts with DAZ (deleted in azoospermia) and is expressed in embryonic stem cells and germ cells. Genomics 83: 834-843, 2004. [PubMed: 15081113] [Full Text: https://doi.org/10.1016/j.ygeno.2003.11.005]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 63-70, 1999. [PubMed: 10231032] [Full Text: https://doi.org/10.1093/dnares/6.1.63]
Toomer, K. A., Yu, M., Fulmer, D., Guo, L., Moore, K. S., Moore, R., Drayton, K. D., Glover, J., Peterson, N., Ramos-Ortiz, S., Drohan, A., Catching, B. J., and 32 others. Primary cilia defects causing mitral valve prolapse. Sci. Transl. Med. 11: eaax0290, 2019. Note: Electronic Article. [PubMed: 31118289] [Full Text: https://doi.org/10.1126/scitranslmed.aax0290]