Study uncovers fatal gene flaw

By MARTIN JOHNSTON health reporter

June Miru has lost a son and five grandsons to a rare genetic disorder that affects mostly males, but is passed on only through their mothers.

In 1988, after the deaths of three of her grandsons, born in September, October and November, doctors started searching for reasons.

Now, nearly four decades after the first of the deaths, they have found the cause of her years of grief: deadly changes in a single gene.

"I was devastated at first because I lost a child in 1963," said Ms Miru, a 59-year-old West Aucklander.

Wati Tito, Ms Miru's first baby, was born two months prematurely. "They said he had brain damage and that if he survived he would be paralysed down one side."

Her four daughters all carry the defective gene, but her other son is unaffected, as are her three surviving grandsons. Five of her granddaughters, aged 3 to 18, have not yet been tested. The sixth is a carrier and was born with moderate abnormalities including deafness, cleft palate and spinal problems.

Ms Miru yesterday welcomed the breakthrough by Otago University child genetics specialist Professor Stephen Robertson, saying it helped to be able to understand why the deaths and deformities had occurred.

His team's findings have been posted on the website of a leading genetics journal, Nature Genetics.

He discovered 17 different mutations of the 8500 DNA codes on a gene called FLNA. These faults can cause a range of mild to fatal birth defects, including missing fingers and toes, ribs so malformed the baby cannot breathe, holes in the heart, and defects in the kidneys, intestines and reproductive organs.

The mutations are passed on only by women, who have a 50-50 chance of giving it to their children. Mostly only males suffer the deformities: females who do are affected less severely. The affected gene is also implicated in causing a rare form of epilepsy in females.

It carries the code for production of a protein, filamin A, that is part of the "scaffolding" of cells.

Professor Robertson's team discovered the protein is also critical for the development of embryos.

"These scaffolding proteins haven't been implicated in that side of biology before. It was quite a surprise," he said.

Professor Robertson, whose ongoing research is financed partly by the Child Health Research Foundation, has developed a tissue/blood test for the extremely rare mutations.

He knows of only 50 families worldwide affected by the syndrome. He has focused on 30 of them, in whom he found the 17 mutations, in the past year.

Twelve geneticists from around the world have contacted him, in the fortnight since his research was publicised to scientists, seeking to have samples from affected families analysed.

"With this new knowledge we hope to be able to progress to more commonly occurring abnormalities like isolated holes in the heart, cleft palate and spina bifida."

The FLNA mutation was unlikely to be preventable by gene therapy because it occurred so early in pregnancy, he said, but his findings could lead to other kinds of preventive treatment.

"Women are encouraged to take folic acid [around the time of becoming pregnant, to prevent spina bifida]. There might be some other sort of intervention discovered through understanding the gene involved in these sorts of processes."