DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

Logan, Clare V.; Murray, Jennie; Parry, David; Robertson, Andrea; Bellelli, Roberto; Tarnauskaitė, Žygimantė; Challis, Rachel; Cleal, Louise; Borel, Valérie; Fluteau, Adeline; Aitman, Tim; Barroso, Inês; Basel, Donald; Bicknell, Louise S.; Goel, Himanshu; Hu, Hao; Huff, Chad; Hutchison, Michele R.; Joyce, Caroline; Knox, Rachel; Lacroix, A.; Langlois, Sylvie; McCandless, Shawn E.; McCarrier, Julie; Metcalfe, Kay; Morrissey, Rose; Murphy, Nuala; Netchine, Irène; O’Çonnell, Susan; Olney, Ann Haskins; Paria, Nandina; Rosenfeld, Jill A.; Sherlock, Mark; Syverson, Erin; White, Perrin C.; Wise, Carol A.; Yu, Yao; Zacharin, Margaret; Banerjee, Indraneel; Reijns, Martin A.M.; Bober, Michael B.; Semple, Robert; Boulton, Simon J.; Rios, Jonathan J.; Jackson, Andrew P.; Aitman, Timothy J.; Biankin, Andrew V.; Cooke, Susanna L.; Humphrey, Wendy Inglis; Martin, Sancha; Mennie, Lynne J.; Meynert, Alison; Miedzybrodzka, Zosia; Murphy, Fiona; Nourse, Craig; Santoyo-López, Javier; Semple, Colin A.; Williams, Nicola

doi:10.1016/j.ajhg.2018.10.024

Cited by 79 publications

(86 citation statements)

References 28 publications

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“…Proteins encoded by MPD disease genes participate in essential cellular processes, including DNA replication (Bicknell, Bongers, et al, ; Bicknell, Walker, et al, ; Burrage et al, ; Fenwick et al, ; Guernsey et al, ; Logan et al, ; Vetro et al, ), DNA damage response signalling and DNA repair (Harley et al, ; Murray et al, , ; O'Driscoll, Ruiz‐Perez, Woods, Jeggo, & Goodship, ; Ogi et al, ; Qvist et al, ; Reynolds et al, ). Collectively, variants in these genes are thought to cause disease by prolonging the cell cycle, with reduced cell proliferation resulting in a smaller number of cells throughout the body and brain, and therefore a smaller person (Klingseisen & Jackson, ).…”

Section: Introductionmentioning

confidence: 99%

Biallelic variants in DNA2 cause microcephalic primordial dwarfism

et al. 2019

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Microcephalic primordial dwarfism (MPD) is a group of rare single‐gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD‐associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)‐dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764‐38_1764‐37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP‐dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.

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Section: Introductionmentioning

confidence: 99%

Biallelic variants in DNA2 cause microcephalic primordial dwarfism

et al. 2019

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“…[48][49][50][51] Fascinatingly, differing mutations in POLE underlie a clinical spectrum that includes FILS syndrome (facial dysmorphism, immunodeficiency, livedo reticularis, and short stature; MIM: 615083) 52 and IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia, and congenital and genitourinary anomalies in males; MIM: 614732), and both diseases are associated with variable immunodeficiency. 36,53 Additionally, a POLE2 (MIM: 602670) mutation has been identified in an individual with combined immunodeficiency, facial dysmorphism, and autoimmunity associated with compromised lymphocyte proliferation. 54 Germline mutations in POLD1 have been described to underlie a range of congenital disorders, including MDP syndrome (mandibular hypoplasia, deafness, and progeroid; MIM: 615381), lipodystrophy, and atypical Werner's syndrome with short stature (MIM: 277700).…”

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confidence: 99%

Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism

Esch

Colnaghi

Freson

et al. 2019

The American Journal of Human Genetics

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Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases a, d, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 3 10 3 nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases d and ε. The DNA polymerase a-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase a-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase a.

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“…In humans, homozygous mutations severely decreasing levels of pol ε are surprisingly not lethal but cause immunodeficiency, facial dysmorphism, livedo, and short stature [81]. Bi-allelic mutations in POLE cause IMAGe syndrome [82]. Mutations in POLE cause the same conditions as some DNA breakage/instability syndromes [83].…”

Section: Discussionmentioning

confidence: 99%

Compensation for the absence of the catalytically active half of DNA polymerase ε in yeast by positively selected mutations inCDC28gene

Stepchenkova

Zhuk

Cui

et al. 2020

Preprint

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DNA polymerase ε (pol ε) participates in the leading DNA strand synthesis in eukaryotes. The catalytic subunit of this enzyme, Pol2, is a fusion of two ancestral B-family DNA polymerases. Paradoxically, the catalytically active N-terminal pol is dispensable, and an inactive C-terminal pol is essential for yeast cell viability. Despite extensive studies of strains without the active N-terminal part (mutation pol2-16), it is still unclear how they survive and what the mechanism is of rapid recovery of initially miserably growing cells. Slow progress is attributed to the difficultly of obtaining strains with the defect. We designed a robust method for the construction of mutants with only the C-terminal part of Pol2 using allele pol2rc-ΔN optimized for high protein production. Colonies bearing pol2rc-ΔN appear three times sooner than colonies of pol2-16 but exhibit similar growth defects: sensitivity to hydroxyurea, chromosomal instability, and an elevated level of spontaneous mutagenesis. UV-induced mutagenesis is partially affected, it is lower only at high doses in some reporters. The analysis of the genomes of pol2rc-ΔN isolates revealed the prevalence of nonsynonymous mutations suggesting that the growth recovery was a result of evolution by positive selection for better growth fueled by variants produced by the elevated mutation rate. Mutations in the CDC28 gene, the primary regulator of the cell cycle, were repeatedly found in independent clones. Genetic analysis established that cdc28 alleles single-handedly improve the growth of pol2rc-ΔN strains and suppress HU-sensitivity. The affected amino acids are located on the Cdc28 molecule’s surfaces that mediate contacts with cyclins and kinase subunits. Our work establishes the significance of the CDC28 gene for the resilience of replication and predicts that changes in mammalian homologs, cyclin-dependent kinases may play a role in remastering replication to compensate for the defects in the leading strand synthesis by the dedicated polymerase.Author SummaryThe catalytic subunit of the leading strand DNA polymerase ε, Pol2, consists of two halves made of two different ancestral B-family DNA polymerases. Counterintuitively, the catalytically active N-terminal half is dispensable while the inactive C-terminal part is required for viability. The corresponding strains show a severe growth defect, sensitivity to replication inhibitors, chromosomal instability, and elevated spontaneous mutagenesis. Intriguingly, the slow-growing mutant strains rapidly produced fast-growing clones. We discovered that the adaptation to the loss of the catalytic N-terminal part of Pol2 occurs during evolution by positive selection for a better growth fueled by variants produced by elevated mutation rates. Mutations in the cell cycle-dependent kinase gene, CDC28, can single-handedly improve the growth of strains lacking the N-terminal part of Pol2. Our study predicts that changes in mammalian homologs of cyclin-dependent kinases may play a role in response to the defects of active leading strand polymerase.

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DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

Cited by 79 publications

References 28 publications

Biallelic variants in DNA2 cause microcephalic primordial dwarfism

Biallelic variants in DNA2 cause microcephalic primordial dwarfism

Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism

Compensation for the absence of the catalytically active half of DNA polymerase ε in yeast by positively selected mutations inCDC28gene

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