Mutations identified that cause rare disease

Coats plus is a rare disorder that affects several parts of the body, including the brain, eye, bone and gastrointestinal tract.

A research team led by Yanick Crow, a geneticist at the University of Manchester, and including Ghada Abdel-Salem from the National Research Centre in Cairo, have found that Coats plus is caused by mutations to a single gene CTC1, which encodes conserved telomere maintenance component 1 (CTC1), and publish their results in Nature Genetics.

The team sequenced each allele of CTC1 in members of ten non-consanguineous families from different ethnic backgrounds diagnosed with Coats plus. They also measured the length of telomeres in three patients with mutated CTC1. Teleomeres are the endcaps of all mammalian chromosomes and protect against tumour growth and form a buffer against several degenerative processes.

The three patients had very short telomeres, around a third of the normal sizes, and the telomere lengths in their parents were in the lower range of normal. The team also observed a significant increase in the number of gamma-H2AX positive cells, which usually indicates ongoing DNA strand breaks.

CTC1 forms a subunit of a complex molecule that stimulates DNA polymerase-α primase, an enzyme that initiates DNA replication — giving CTC1 an extra role in DNA metabolism besides protecting telomeres.

This work "represents the first recording of mutations in genes encoding CST complex proteins in human disease," explains Crow. "The finding of markedly shortened telomeres in affected patients confirms an important role for the CST complex in telomere maintenance."

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