Alternative titles; symbolsKASH DOMAIN-CONTAINING PROTEIN 5; KASH5HGNC Approved Gene Symbol: KASH5Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38)...
Alternative titles; symbols
HGNC Approved Gene Symbol: KASH5
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,388,217-49,418,001 (from NCBI)
CCDC155 links the nucleoskeleton and cytoskeleton by interacting with the inner nuclear membrane protein SUN1 (607723) and recruiting the cytoplasmic protein dynein (see 600112) (Morimoto et al., 2012; Horn et al., 2013).
▼ Cloning and Expression
Morimoto et al. (2012) cloned mouse Ccdc155, which they called Kash5. The deduced 648-amino acid protein contains a central coiled-coil domain and a C-terminal Klarsicht/Anc1/SYNE (see SYNE1, 608441) homology (KASH) domain consisting of a transmembrane region followed by a luminal region. Database analysis revealed that KASH5 was highly conserved among vertebrates, including human. RT-PCR analysis detected Kash5 expression in mouse testis and early ootidogenesis ovary only. Immunostaining experiments revealed that Kash5 was a telomere-associated protein in both male and female early meiosis. Kash5 showed dynamic expression from meiotic S phase to meiosis I in mouse spermatocytes and oocytes. It was not detected in meiotic S phase, then became visible at the ends of chromosomes throughout pachytene until the diplotene stage. Kash5 was undetectable again in metaphase I, when telomeres were completely detached from the nuclear envelope (NE).
Horn et al. (2013) reported that mouse and human KASH5 have calculated molecular masses of 64.4 kD and 62.7 kD, respectively. Both proteins have an N-terminal EF hand-like sequence, a central coiled-coil domain, and a C-terminal KASH domain. Human and mouse Kash5 share significant homology with zebrafish 'futile cycle' (fue), an NE constituent that binds dynein and is essential for pronuclear migration in fertilized eggs. Mouse Kash5 localized to outer nuclear membranes in transfected HeLa and HEK293 cells. Immunofluorescence analysis and RT-PCR revealed Kash5 expression in adult mouse testis and bone marrow, as well as in fetal liver. In testis, Kash5 was expressed in spermatocytes in meiotic prophase I.
Gross (2018) mapped the CCDC155 gene to chromosome 19q13.33 based on an alignment of the CCDC155 sequence (GenBank BC029811) with the genomic sequence (GRCh38).
▼ Gene Function
Morimoto et al. (2012) found that Kash5 interacted directly with Sun1, forming a complex at the NE attachment sites of meiotic telomeres. Expression analysis in mouse spermatocytes confirmed that Kash5 localized to the NE near telomeres through direct interaction with Sun1 in early meiosis, and that Sun1 was essential for this localization. Pull-down assays with mouse testis cytoplasmic extracts revealed that the Sun1-Kash5 complex interacted with cytoplasmic dynein-dynactin (see 601143) complexes. Live-imaging analysis suggested that meiosis-specific chromosome dynamics was driven by microtubule-induced force, presumably through the telomere-Sun1-Kash5-dynactin interaction.
Horn et al. (2013) found that localization of mouse Kash5 at the outer nuclear membranes of transfected cells was dependent on its KASH domain and Sun1. The coiled-coil domain of Kash5 was involved in interaction with dynein, as well as self-association to form oligomers. Analyses of testis cryosections and spermatocyte spreads showed that Kash5 and Sun1 colocalized precisely in spermatocyte NEs, forming a transluminal linker of the nucleoskeleton and cytoskeleton (LINC) complex that appeared as a ring-like structure and spanned nuclear membranes.
▼ Animal Model
Horn et al. (2013) found that homozygous Kash5-knockout mice had normal morphology, no lethal developmental defects, no obvious hematologic pathologies, and normal life span. However, both male and female homozygous knockout mice were infertile. In homozygous knockout females, ovaries were barely visible after necropsy and devoid of follicles. Homozygous knockout males had dramatically reduced testis size compared with wildtype. Histologic analysis revealed normal tissue organization in Kash5-knockout testis, but defects in seminiferous tubules containing numerous cells that were TUNEL positive compared with wildtype. In knockout testis, numerous leptotene/zygotene spermatocytes were evident, but pachytene spermatocytes were absent. Microscopic examination of spermatocytes showed that Kash5 deficiency caused a defect in homologous pairing of chromosomes during meiosis. Further analysis showed that DNA double-strand breaks (DSBs) were never resolved and accumulated in Kash5-knockout spermatocytes. In knockout spermatocytes, Sun1 appeared in single foci with no discernible substructure, the telomere association with Sun1 was reduced drastically, and cytoplasmic dynein was no longer recruited to telomere attachment sites at the NE place, causing arrest of meiotic progression.