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A fresh cup of DCAF: DCAF13 implicated in a neuromuscular disorder

European Journal of Human Genetics volume 31, pages 613–614 (2023)Cite this article

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DCAF13 has traditionally been studied in the context of reproduction and development. Its expression peaks in the morula as the pre-implantation zygotic cells undergo compaction to create the blastocyst [1]. Dcaf13 knock-out leads to embryonic lethality in mouse while RNAi mediated downregulation in Caenorhabditis elegans results in stunted growth, developmental delay, and reduced fertility [2]. Within the oocytes, DCAF13 localizes to the nucleolus and is involved in ribosomal RNA processing as well as chromatin compaction [3]. In this issue, Manzoor et al. describe a novel association of DCAF13 with a neuromuscular disorder (NMD) characterized by waddling gait and muscle weakness [4].

Manzoor et al. discovered this novel biallelic missense variant in DCAF13 in a consanguineous family from Pakistan. Harnessing the dual power of a family-based study design and exome sequencing, they found this variant rs1209794872 within the region of homozygosity shared among the four affected individuals and it perfectly segregated with the disease in this family. This variant NM_015420.7c.907G>A replaces an aspartic acid residue with an asparagine in the third WD40 domain of DCAF13 protein, retaining the polarity but altering the charge at this position, thus potentially reducing its stability. The variant is extremely rare (allele frequency 0.000007081 and 0.000003983 in gnomAD and ExAC databases, respectively; none found homozygous) and absent in the 600 ethnically matched chromosomes they genotyped as controls. Aspartic acid (Asp) at this position is remarkably well conserved across taxa, although the sequence identity progressively decreases for the whole protein (87.4%, 68.1%, 42.7%, 17.8% and 15.3% for primates, mammals, vertebrates, animals, and eukaryotes, respectively). Such strong selection pressure operative on a particular site points to its likely functional relevance. Interestingly, only three benign and fourteen variants of uncertain significance have thus far been listed in Clinvar, making this the first likely pathogenic DCAF13 variant to be reported.

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References

  1. Zhang YL, Zhao LW, Zhang J, Le R, Ji SY, Chen C, et al. DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development. EMBO J. 2018;37:e98981.

  2. Durkan A, Byrnes C, Cooper E, Hally A, Sullivan-Brown J, Sowa J. DCAF-13 is required for C. elegans growth, development, and fertility. MicroPubl Biol. 2022. https://doi.org/10.17912/micropub.biology.000641.

  3. Zhang J, Zhang YL, Zhao LW, Guo JX, Yu JL, Ji SY, et al. Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing. Cell Death Differ. 2019;26:1251–66.

    Article  CAS  PubMed  Google Scholar 

  4. Manzoor H, Zahid H, Emerling CA, Kumar KR, Hussain HMJ, Seo GH, et al. A biallelic variant of DCAF13 implicated in a neuromuscular disorder in humans. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01319-7.

  5. Zhang J, Zhang YL, Zhao LW, Pi SB, Zhang SY, Tong C, et al. The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation. Cell Mol Life Sci. 2020;77:2181–97.

    Article  CAS  PubMed  Google Scholar 

  6. Yan X, Rong M, Zhou Q, Zhang C. DCAF13 is essential for the pathogenesis of preeclampsia through its involvement in endometrial decidualization. Mol Cell Endocrinol. 2022;556:111741.

    Article  CAS  PubMed  Google Scholar 

  7. Shan BQ, Wang XM, Zheng L, Han Y, Gao J, Lv MD, et al. DCAF13 promotes breast cancer cell proliferation by ubiquitin inhibiting PERP expression. Cancer Sci. 2022;113:1587–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu J, Li H, Mao A, Lu J, Liu W, Qie J, et al. DCAF13 promotes triple-negative breast cancer metastasis by mediating DTX3 mRNA degradation. Cell Cycle. 2020;19:3622–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. J Neuromuscul Dis. 2015;2:73–85.

    Article  PubMed  Google Scholar 

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  1. Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

    Aniket Bhattacharya

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Correspondence to Aniket Bhattacharya.

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Bhattacharya, A. A fresh cup of DCAF: DCAF13 implicated in a neuromuscular disorder. Eur J Hum Genet 31, 613–614 (2023). https://doi.org/10.1038/s41431-023-01340-w

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