DNA polymerase, POLA1  mutation linked to intellectual disability

DNA polymerase, POLA1 mutation linked to intellectual disability

Researchers have discovered a new genetic defect which causes a form of intellectual disability; a finding that will improve screening programmes and help to end a 'diagnostic odyssey' for families across the globe.

'X-linked syndromal intellectual disability' (XLID) affects around 3% of the global population with the underlying genetic mutations being carried and passed on by unaffected females via their X-chromosome (human females possess two copies of the X chromosome, while males only have one).

These 'carrier' mothers have a 50% chance of passing on the mutated genes to their offspring but interestingly, for this form of XLID, symptoms are only observed in males. These can include behavioral issues, stunted growth, and smaller than average brains and testes.

Up until now, researchers had identified 141 genes thought to cause XLID but there are still many cases of unknown genetic cause.

In a paper published in the journal, American Journal of Human Genetics, researchers have identified a new gene defect, which will help clinicians around the world accurately diagnose further cases of XLID.

The senior author said: "This is a completely new gene target which can now be incorporated into existing screening programmes worldwide to aid future diagnoses and accurate genetic counselling along with patient management."

The gene identified makes a fundamental component of the machinery our cells use to replicate their DNA during cell division, called "DNA Polymerase a-primase [alpha-primase]". This was an unexpected finding as it was assumed that any impairment to this function would be incompatible with life.

Therefore, the researchers faced the challenge of proving that the mutations found in the affected individuals did impair DNA Polymerase a-primase function [alpha-primase] but without destroying it completely. This was facilitated by analysing cells from the patients' blood using a recently developed complex technique called "DNA Fibre Combing".

Here, individual DNA strands are painstakingly isolated on specially formulated microscope slides, following staining with chemical markers, enabling the researchers to monitor different aspects of the DNA replication process at a minute level. While they were surprised to find that the rate of cell division was unaffected, the highly sensitive analysis conducted by the team showed that several replication parameters of the DNA molecules from these cells were highly problematic.

The authors 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 α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals.