Alternative titles; symbols
HGNC Approved Gene Symbol: DZIP1L
Cytogenetic location: 3q22.3 Genomic coordinates (GRCh38) : 3:138,061,990-138,115,608 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q22.3 | Polycystic kidney disease 5 | 617610 | Autosomal recessive | 3 |
DZIP1L appears to play a role in ciliary structure and/or function (Lu et al., 2017).
Lu et al. (2017) cloned human DZIP1L. The deduced 767-amino acid protein has a C2H2-type zinc finger motif near its N terminus, followed by a series of coiled-coil domains. Immunohistochemical analysis detected DZIP1L at centrioles and basal bodies in human dermal fibroblasts, mouse embryonic fibroblasts, and mouse kidney inner medullary collecting duct (IMDC3) cells. Dzip1l localized to centrioles throughout the cell cycle, and it colocalized with markers of both subdistal and distal appendages of mother centrioles in IMDC3 cells. Human DZIP1L colocalized with TCTN1 (609863), a marker of the ciliary transition zone, in ciliated human fibroblasts and human retinal pigment epithelial cells. Western blot analysis of human dermal fibroblasts detected DZIP1L at an apparent molecular mass between 100 and 150 kD.
Lu et al. (2017) determined that the DZIP1L gene has 16 exons.
Lu et al. (2017) stated that the DZIP1L gene maps to chromosome 3q22.1-q23. The mouse Dzip1l gene maps to chromosome 9.
Hartz (2017) mapped the DZIP1L gene to chromosome 3q22.3 based on an alignment of the DZIP1L sequence (GenBank AK057406) with the genomic sequence (GRCh38).
Using DZIP1L as bait in a yeast 2-hybrid screen of human testis, lung, and brain, Lu et al. (2017) identified SEPT2 (601506), which functions in cilia as part of the periciliary diffusion barrier at the transition zone. Coimmunoprecipitation analysis confirmed interaction of epitope-tagged and endogenous DZIP1L and SEPT2 proteins. Mutation analysis showed that a 165-residue N-terminal fragment of DZIP1L lacking the zinc finger and coiled-coil domains interacted with SEPT2.
In 7 patients from 4 unrelated consanguineous families with polycystic kidney disease-5 (PKD5; 617610), a form of autosomal recessive PKD (ARPKD), Lu et al. (2017) identified homozygous missense or truncating mutations in the DZIP1L gene (617570.0001-617570.0004). Mutations in the first 2 families, which were found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Mutations in the other 2 families were found by direct sequencing of the DZIP1L gene in 218 unrelated subjects with suspected ARPKD or next-generation sequencing of a targeted gene panel in 1,330 individuals with a similar phenotype. Fibroblasts derived from 1 of the patients with a truncating mutation showed no obvious differences in the percentage of ciliated cells, cilia morphology, or localization of several markers of cilia and basal bodies compared to controls. However, the cilia showed decreased accumulation of PKD1 (601313) and PKD2 (173910) along the ciliary membrane compared to controls. These findings suggested that, in the absence of correct DZIP1L function, the ciliary-membrane distribution of PKD1 and PKD2 is compromised, possibly reflecting a defect in the barrier function of the transition zone.
In a recessive N-ethyl-N-nitrosourea mutagenesis screen, Lu et al. (2017) identified the mouse 'warpy' (wpy) mutant and found that wpy was a nonsense mutation (Q375X) in a region of the Dzip1l gene encoding the coiled-coil domains. Dzip1l wpy/wpy mutants showed widespread dysmorphologies, including highly penetrant polydactyly of all 4 limbs, gross eye abnormalities, and craniofacial defects, including cleft lip/palate. Some of the mouse mutants showed embryonic death. On an outbred genetic background, Dzip1l wpy/wpy mice were obtained at the expected mendelian frequency, although they failed to thrive and were sacrificed by postnatal day 21. These Dzip1l wpy/wpy mice showed early-onset progressive cystic kidney disease, with cysts arising from collecting ducts and proximal tubules. There were also subtle signs of hepatic abnormalities, with an excess of bile ducts but no frank fibrosis. Dzip1l wpy/wpy fibroblasts showed evidence of a defect in Shh (600725) signaling and abnormal ciliary membrane distribution of Pc1 (PKD1; 601313) and Pc2 (PKD2; 173910), possibly reflecting a defect in the barrier function of the transition zone. Inactivation of zebrafish dzip1l also caused phenotypes consistent with ciliary dysfunction.
In 3 sibs, born of consanguineous Turkish parents (family B16), with polycystic kidney disease-5 (PKD5; 617610), Lu et al. (2017) identified a homozygous c.269C-T transition (c.269C-T, NM_173543.2) in exon 2 of the DZIP1L gene, resulting in an ala90-to-val (A90V) substitution at a highly conserved residue. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 2 sisters, born of consanguineous Arab parents (family A3533), with polycystic kidney disease-5 (PKD5; 617610), Lu et al. (2017) identified a homozygous c.273G-C transversion (c.273G-C, NM_173543.2) in exon 2 of the DZIP1L gene, resulting in a gln91-to-his (Q91H) substitution at a highly conserved residue. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In a boy, born of consanguineous Palestinian parents (family B155), with polycystic kidney disease-5 (PKD5; 617610), Lu et al. (2017) identified a homozygous c.463C-T transition (c.463C-T, NM_173543.2) in exon 2 of the DZIP1L gene, resulting in a gln155-to-ter (Q155X) substitution. The mutation was not found in the ExAC database. Western blot analysis of patient cells showed absence of the full-length protein.
In a girl, born of consanguineous Egyptian parents (family B8031), with polycystic kidney disease-5 (PKD5; 617610), Lu et al. (2017) identified a homozygous 2-bp deletion (c.1061_1062del, NM_173543.2) in exon 7 of the DZIP1L gene, resulting in a frameshift and premature termination (Glu354AlafsTer39). The mutation was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
Hartz, P. A. Personal Communication. Baltimore, Md. 7/12/2017.
Lu, H., Galeano, M. C. R., Ott, E., Kaeslin, G., Kausalya, P. J., Kramer, C., Ortiz-Bruchle, N., Hilger, N., Metzis, V., Hiersche, M., Tay, S. Y., Tunningley, R., and 21 others. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nature Genet. 49: 1025-1034, 2017. [PubMed: 28530676] [Full Text: https://doi.org/10.1038/ng.3871]