Limits...
DNA polymerase- α regulates type I interferon activation through cytosolic RNA:DNA synthesis

View Article: PubMed Central - PubMed

ABSTRACT

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations disrupting nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts expression of POLA1, the gene encoding the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency results in increased type I interferon production. This enzyme is necessary for RNA:DNA primer synthesis during DNA replication and strikingly, POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Altogether, this work identified POLA1 as a critical regulator of the type I interferon response.

No MeSH data available.


Whole genome sequencing identifies a recurrent intronic mutation as the cause of XLPDRWhole genome sequencing followed by targeted genotyping was performed. Pedigrees of eleven families with XLPDR analyzed here are shown, including seven new cases (place of origin is noted). Probands and relatives examined elsewhere in the paper are indicated (P1 to P21, and F1 to F3). Red arrows depict the probands whose DNA was analyzed by whole genome sequencing. Possible cases or carriers are indicated in gray. Results of genotyping for the intronic mutation in POLA1 are noted (A, wild-type allele; G, XLPDR-associated allele).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4836962&req=5

Figure 1: Whole genome sequencing identifies a recurrent intronic mutation as the cause of XLPDRWhole genome sequencing followed by targeted genotyping was performed. Pedigrees of eleven families with XLPDR analyzed here are shown, including seven new cases (place of origin is noted). Probands and relatives examined elsewhere in the paper are indicated (P1 to P21, and F1 to F3). Red arrows depict the probands whose DNA was analyzed by whole genome sequencing. Possible cases or carriers are indicated in gray. Results of genotyping for the intronic mutation in POLA1 are noted (A, wild-type allele; G, XLPDR-associated allele).

Mentions: Prior linkage analyses had mapped the XLPDR locus to a 4.9 Mb interval of the X chromosome20. However, Sanger and exome capture sequencing failed to identify any causal mutation. For the genetic analysis performed here, we included five of the seven known XLPDR families, as well as seven new families not previously reported (Fig. 1). The additional probands all displayed characteristic pigmentary changes of XLPDR, and most had the distinctive facies (Supplementary Fig. 1a). Skin biopsies from two new probands demonstrated the presence of melanophages and amyloid-like material in the upper dermis, as has been previously reported in XLPDR10 (Supplementary Fig. 1b).


DNA polymerase- α regulates type I interferon activation through cytosolic RNA:DNA synthesis
Whole genome sequencing identifies a recurrent intronic mutation as the cause of XLPDRWhole genome sequencing followed by targeted genotyping was performed. Pedigrees of eleven families with XLPDR analyzed here are shown, including seven new cases (place of origin is noted). Probands and relatives examined elsewhere in the paper are indicated (P1 to P21, and F1 to F3). Red arrows depict the probands whose DNA was analyzed by whole genome sequencing. Possible cases or carriers are indicated in gray. Results of genotyping for the intronic mutation in POLA1 are noted (A, wild-type allele; G, XLPDR-associated allele).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4836962&req=5

Figure 1: Whole genome sequencing identifies a recurrent intronic mutation as the cause of XLPDRWhole genome sequencing followed by targeted genotyping was performed. Pedigrees of eleven families with XLPDR analyzed here are shown, including seven new cases (place of origin is noted). Probands and relatives examined elsewhere in the paper are indicated (P1 to P21, and F1 to F3). Red arrows depict the probands whose DNA was analyzed by whole genome sequencing. Possible cases or carriers are indicated in gray. Results of genotyping for the intronic mutation in POLA1 are noted (A, wild-type allele; G, XLPDR-associated allele).
Mentions: Prior linkage analyses had mapped the XLPDR locus to a 4.9 Mb interval of the X chromosome20. However, Sanger and exome capture sequencing failed to identify any causal mutation. For the genetic analysis performed here, we included five of the seven known XLPDR families, as well as seven new families not previously reported (Fig. 1). The additional probands all displayed characteristic pigmentary changes of XLPDR, and most had the distinctive facies (Supplementary Fig. 1a). Skin biopsies from two new probands demonstrated the presence of melanophages and amyloid-like material in the upper dermis, as has been previously reported in XLPDR10 (Supplementary Fig. 1b).

View Article: PubMed Central - PubMed

ABSTRACT

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations disrupting nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts expression of POLA1, the gene encoding the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency results in increased type I interferon production. This enzyme is necessary for RNA:DNA primer synthesis during DNA replication and strikingly, POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Altogether, this work identified POLA1 as a critical regulator of the type I interferon response.

No MeSH data available.