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Mild MDPL in a patient with a novel de novo missense variant in the Cys-B region of POLD1


DNA polymerase δ is one of the three main enzymes responsible for DNA replication. POLD1 heterozygous missense variants in the exonuclease domain result in a cancer predisposition phenotype. In contrast, heterozygous variants in POLD1 polymerase domain have more recently been shown to be the underlying basis of the distinct autosomal dominant multisystem lipodystrophy disorder, MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome OMIM # 615381), most commonly a recurrent in-frame deletion of serine at position 604, accounting for 18 of the 21 reported cases of this condition. One patient with an unusually severe phenotype has been reported, caused by a de novo c. 3209 T > A, (p.(Ile1070Asn)) variant in the highly conserved CysB motif in the C-terminal of the POLD1 protein. This region has recently been shown to bind an iron-sulphur cluster of the 4Fe-4S type. This report concerns a novel de novo missense variant in the CysB region, c.3219 G > C, (p.(Ser1073Arg)) in a male child with a milder phenotype. Using in silico analysis in the context of the recently published structure of human Polymerase δ holoenzyme, we compared these and other variants which lie in close proximity but result in differing degrees of severity and varying features. We hypothesise that the c.3219 G > C, (p.(Ser1073Arg)) substitution likely causes reduced binding of the iron-sulphur cluster without significant disruption of protein structure, while the previously reported c.3209 T > A (p.(Ile1070Asn)) variant likely has a more profound impact on structure and folding in the region. Our analysis supports a central role for the CysB region in regulating POLD1 activity in health and disease.

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Fig. 1: Architecture of human DNA polymerase δ catalytic subunit and alignment of the CysB motif in POLD1 orthologues.
Fig. 2: Facial features of index case, age 5 years.
Fig. 3: Structure of POLD1 and CysB variants.
Fig. 4: Physicochemical properties of the CysA and CysB regions of POLD1.

Data availability

The variant identified in this project has been submitted to a publicly accessible genetic variant database, ClinVar. The ClinVar accession number is SUB9578857.


  1. Weedon MN, Ellard S, Prindle MJ, Caswell R, Allen HL, Oram R, et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet. 2013;45:947–50.

    CAS  Article  Google Scholar 

  2. Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, et al. A Novel Syndrome of Mandibular Hypoplasia, Deafness, and Progeroid Features Associated with Lipodystrophy, Undescended Testes, and Male Hypogonadism. J Clin Endocrinol Metab. 2010;95:E192–7.

    CAS  Article  Google Scholar 

  3. Pelosini C, Martinelli S, Ceccarini G, Magno S, Barone I, Basolo A, et al. Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome. Metab Clin Exp. 2014;63:1385–9.

    CAS  Article  Google Scholar 

  4. Fiorillo C, D’Apice MR, Trucco F, Murdocca M, Spitalieri P, Assereto S, et al. Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene. DNA Cell Biol. 2018;37:1061–7.

    CAS  Article  Google Scholar 

  5. Okada A, Kohmoto T, Naruto T, Yokota I, Kotani Y, Shimada A, et al. The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection. Human Genome Variation [Internet]. 2017[cited 2019 May 28];4.

  6. Wang LR, Radonjic A, Dilliott AA, McIntyre AD, Hegele RA. A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome. J Investig Med High Impact Case Rep. 2018;6:232470961878677.

    Article  Google Scholar 

  7. Reinier F, Zoledziewska M, Hanna D, Smith JD, Valentini M, Zara I, et al. Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies. Metab Clin Exp. 2015;64:1530–40.

    CAS  Article  Google Scholar 

  8. Lessel D, Hisama FM, Szakszon K, Saha B, Sanjuanelo AB, Salbert BA, et al. POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome. Hum Mutat. 2015;36:1070–9.

    CAS  Article  Google Scholar 

  9. Elouej S, Beleza-Meireles A, Caswell R, Colclough K, Ellard S, Desvignes JP, et al. Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL). Metabolism 2017;71:213–25.

    CAS  Article  Google Scholar 

  10. Netz DJA, Pierik AJ, Stümpfig M, Bill E, Sharma AK, Pallesen LJ. et al. A Bridging [4Fe-4S] Cluster and Nucleotide Binding Are Essential for Function of the Cfd1-Nbp35 Complex as a Scaffold in Iron-Sulfur Protein Maturation. J Biol Chem. 2012;287:12365–78.

    CAS  Article  Google Scholar 

  11. Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T, et al. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016;44:W344–350. 08

    CAS  Article  Google Scholar 

  12. Lancey C, Tehseen M, Raducanu V-S, Rashid F, Merino N, Ragan TJ, et al. Structure of the processive human Pol δ holoenzyme. Nat Commun. 2020;11:1109. 28

    CAS  Article  Google Scholar 

  13. Cui Y, Keles S, Charbonnier L-M, Julé AM, Henderson L, Celik SC, et al. Combined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1. J Allergy Clin Immunol. 2020;145:391–401.e8.

    CAS  Article  Google Scholar 

  14. Ajluni N, Meral R, Neidert AH, Brady GF, Buras E, McKenna B, et al. Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort. Clin Endocrinol. 2017;86:698–707.

    CAS  Article  Google Scholar 

  15. Oh D-Y, Matsumoto Y, Kitajiri S-I, Kim NKD, Kim MY, Kim AR, et al. POLD1 variants leading to reduced polymerase activity can cause hearing loss without syndromic features. Hum Mutat. 2020;41:913–20.

    CAS  Article  Google Scholar 

  16. Sasaki H, Yanagi K, Ugi S, Kobayashi K, Ohkubo K, Tajiri Y, et al. Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene. Endocr J. 2017;65:227–38.

    Article  Google Scholar 

  17. Gao S, Zhang X, Song Q, Liu J, Ji X, Wang P. POLD1 deficiency is involved in cognitive function impairment in AD patients and SAMP8 mice. Biomed Pharmacother. 2019;114:108833.

    CAS  Article  Google Scholar 

  18. Jozwiakowski SK, Kummer S, Gari K. Human DNA polymerase delta requires an iron–sulfur cluster for high-fidelity DNA synthesis. Life Sci Alliance. 2019;2:e201900321.

    Article  Google Scholar 

  19. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46:944–50.

    CAS  Article  Google Scholar 

  20. Dron JS, Wang J, McIntyre AD, Iacocca MA, Robinson JF, Ban MR, et al. Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. BMC Med Genom. 2020;13:23.

    Article  Google Scholar 

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The authors of this paper wish to acknowledge the patient and family for their participation in this study. The authors would also like to thank Andrew Hattersley for his critical review of the paper. The authors of this paper wish to acknowledge the Fondation Bettencourt-Schueller, MSD-France and the patient organization “S’entendre” for their financial supports.

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Correspondence to Sandrine Marlin.

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Chopra, M., Caswell, R., Barcia, G. et al. Mild MDPL in a patient with a novel de novo missense variant in the Cys-B region of POLD1. Eur J Hum Genet 30, 960–966 (2022).

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