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KH RNA binding domain containing, signal transduction associated 1 OKDB#: 4180
 Symbols: KHDRBS1 Species: human
 Synonyms: p62, p68, Sam68  Locus: 1p35.2 in Homo sapiens

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
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DNA Microarrays
link to BioGPS
General Comment

NCBI Summary: This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3'-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]
General function DNA repair, RNA binding
Comment Sam68 Is Required for DNA Damage Responses via Regulating Poly(ADP-ribosyl)ation. Sun X et al. (2016) The rapid and robust synthesis of polymers of adenosine diphosphate (ADP)-ribose (PAR) chains, primarily catalyzed by poly(ADP-ribose) polymerase 1 (PARP1), is crucial for cellular responses to DNA damage. However, the precise mechanisms through which PARP1 is activated and PAR is robustly synthesized are not fully understood. Here, we identified Src-associated substrate during mitosis of 68 kDa (Sam68) as a novel signaling molecule in DNA damage responses (DDRs). In the absence of Sam68, DNA damage-triggered PAR production and PAR-dependent DNA repair signaling were dramatically diminished. With serial cellular and biochemical assays, we demonstrated that Sam68 is recruited to and significantly overlaps with PARP1 at DNA lesions and that the interaction between Sam68 and PARP1 is crucial for DNA damage-initiated and PARP1-conferred PAR production. Utilizing cell lines and knockout mice, we illustrated that Sam68-deleted cells and animals are hypersensitive to genotoxicity caused by DNA-damaging agents. Together, our findings suggest that Sam68 plays a crucial role in DDR via regulating DNA damage-initiated PAR production.//////////////////
Cellular localization Nuclear
Ovarian function
Expression regulated by
Ovarian localization Oocyte
Follicle stages
Phenotypes POF (premature ovarian failure)
Mutations 2 mutations

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development. Bianchi E et al. Sam68 is a multifunctional RNA binding protein highly expressed in the gonads, whose ablation causes male infertility. Herein, we have investigated Sam68 expression in the adult ovary and its function in female fertility. Immunohistochemistry showed that Sam68 was localized in the nucleus of oocytes and follicular cells at all stages of folliculogenesis. Sam68(-/-) females were severely subfertile, they showed a delay in the age of first pregnancy, increased breeding time for successful pregnancy and yielded smaller litters. Morphological analyses indicated a significant reduction in the number of secondary and pre-antral follicles in the ovary. These defects were associated with alteration of estrus cycles and reduced number of ovulated oocytes, which were only partially restored by administration of exogenous gonadotropins. Crosslink/immunoprecipitation experiments showed that Sam68 directly binds the mRNAs for the follicle stimulating hormone (FSH) and the luteinizing hormone (LH) receptors (Fshr and Lhcgr), which were downregulated in ovaries of adult knockout females. Stimulation of immature females with the FSH-like PMSG, or of follicular cells with the FSH second messenger analogue 8Br-cAMP, caused upregulation of Sam68. The increase in Sam68 levels paralleled that of the Fshr and Lhcgr mRNAs in the preovulatory follicle and was required to allow accumulation of these transcripts in follicular cells. These studies identify a new crucial function of Sam68 in the regulation of female fertility and indicate that this protein is required to insure proper expression of the gonadotropin receptor transcripts in preovulatory follicles in adult ovary.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Sequence variants of KHDRBS1 as high penetrance susceptibility risks for primary ovarian insufficiency by mis-regulating mRNA alternative splicing /////STUDY QUESTION Does a novel heterozygous KHDRBS1 variant, identified using whole-exome sequencing (WES) in two patients with primary ovarian insufficiency (POI) in a pedigree, cause defects in mRNA alternative splicing? SUMMARY ANSWER The heterozygous variant of KHDRBS1 was confirmed to cause defects in alternative splicing of many genes involved in DNA replication and repair. WHAT IS KNOWN ALREADY Studies in mice revealed that Khdrbs1 deficient females are subfertile, which manifests as delayed sexual maturity and significantly reduced numbers of secondary and pre-antral follicles. No mutation of KHDRBS1, however, has been reported in patients with POI. STUDY DESIGN SIZE, DURATION This genetic and functional study used WES to find putative mutations in a POI pedigree. Altogether, 215 idiopathic POI patients and 400 healthy controls were screened for KHDRBS1 mutations. PARTICIPANTS/MATERIALS, SETTING, METHODS Two POI patients were subjected to WES to identify sequence variants. Mutational analysis of the KHDRBS1 gene in 215 idiopathic POI patients and 400 healthy controls were performed. RNA-sequencing was carried out to find the mis-regulation of gene expression due to KHDRBS1 mutation. Bioinformatics was used to analyze the change in alternative splicing events. MAIN RESULTS AND THE ROLE OF CHANCE We identified a heterozygous mutation (c.460A > G, p.M154V) in KHDRBS1 in two patients. Further mutational analysis of 215 idiopathic POI patients with the KHDRBS1 gene found one heterozygous mutation (c.263C > T, p.P88L). We failed to find these two mutations in 400 healthy control women. Using RNA-sequencing, we found that the KGN cells expressing the M154V KHDRBS1 mutant had different expression of 66 genes compared with wild-type (WT) cells. Furthermore, 145 genes were alternatively spliced in M154V cells, and these genes were enriched for DNA replication and repair function, revealing a potential underlying mechanism of the pathology that leads to POI. LIMITATIONS: REASONS FOR CAUTION Although the in vitro assays demonstrated the effect of the KHDRBS1 variant on alternative splicing, further studies are needed to validate the in vivo effects on germ cell and follicle development. WIDER IMPLICATIONS OF THE FINDINGS This finding provides researchers and clinicians a better understanding of the etiology and molecular mechanism of POI.

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created: Feb. 4, 2010, 10:08 a.m. by: hsueh   email:
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last update: Sept. 20, 2017, 4:11 p.m. by: hsueh    email:

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