Alt. symbols: POLA | NSX | p180

Approved name: DNA polymerase alpha 1, catalytic subunit
Alt. names: polymerase (DNA directed), alpha, N syndrome (mental retardation, malformations, chromosome breakage), polymerase (DNA) alpha 1, catalytic subunit

Location: Xp22.11: 24693873 - 24996986 (+)
Gene type: protein_coding, 14 transcripts.

Scores: LoFtool: 0.099300 | pLI: 0.99999952 | LOEUF: 0.051

HGNC: 9173

NCBI: 5422, RefSeq: NG_016798.2

Ensembl: ENSG00000101868.13

LRG_ | Status: none

OMIM: 312040

Expression | ProteinAtlas

POLA1 encodes the catalytic subunit of the DNA polymerase alpha-primase complex, which plays an essential role in initiation of DNA synthesis. During S phase, this complex is recruited to replication forks via direct interactions with MCM10 and WDHD1. The primase subunit initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by polymerase alpha before transfer to polymerase delta and polymerase epsilon for processive lagging and leading strand synthesis, respectively. Polymerase alpha has limited processivity and lacks intrinsic proofreading (3' exonuclease) activity, making it poorly suited for replicating long tracts. In the cytosol, polymerase alpha is also responsible for synthesizing a substantial proportion of the physiological concentration of RNA:DNA hybrids, thought essential for preventing spontaneous activation of type I interferon (IFN) responses (PMID: 27019227).

Hemizygous missense and splice site mutations in POLA1 in five unrelated families have been associated with Van Esch-O'Driscoll syndrome [MIM:301030], a syndrome featuring varying degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations. This phenotype is similar to mutations in other components of the DNA replication machinery. Carrier females were unaffected and showed significant to complete skewing of X-inactivati on. Affected patient cells showed reduced levels of productive replication initiation under conditions of unperturbed exponential growth (PMID: 31006512). A unique hypomorphic intronic mutation (NM_016937.3:c.1375–354A>G) predicted to alter POLA1 splicing has been linked to X-linked reticulate pigmentary disorder (PDR) with systemic manifestations [MIM: 301220]. This condition more severely affects hemizygous males than heterozygous females. Affected males have a characteristic facies (frontally upswept hair and flared eyebrows), generalized reticular pigmentation abnormalities of the skin, early onset recurrent respiratory infections, failure to thrive due to inflammatory gastroenteritis or colitis, and may develop corneal scarring. Carrier females may be unaffected or only show pigmentary abnormalities along the lines of Blaschko in a manner similar to incontinentia pigmenti. Patients have essentially normal immunologic parameters, but show elevated plasma type I IFN gene signatures, decreased plasma IL-17A and IFN-gamma levels, which may predispose to infections (PMID: 27019227). [Load More]