A simple joy, often taken for granted, is to unexpectedly run into a friend or a relative at a train station or market. Recognising a familiar face in an unfamiliar context or crowded place gives most of us unalloyed pleasure.
We should give thanks to our MCTP2 gene for this ability. According to research published in this month’s issue of the journal Genetics, by researchers led by Ye Rao of Capital Medical University, Beijing, when this gene is mutated the ability to recognise faces is severely impaired.
Individuals with the misfortune of carrying the mutant gene took much longer than is socially acceptable to recognise people with whom they were expected to be familiar — such as spouses, siblings, and children — while they confused strangers with familiar people.
This disorder is called prosopagnosia, or face blindness. Its prevalence worldwide is estimated to be 1.8-2.9% in the general population. Prosopagnosia is one form of visual agnosia, or inability to identify everyday items just by looking at them.
The MCTP2 gene is thus the first found to be required for a higher form of visual social cognition in humans.
Face recognition and a gene
The researchers identified a family of 35 individuals spread across three generations. The members of its eldest generation were all older than 60 years. Nine members of the family had daily problems with recognising faces. They also performed very poorly on a standardised face recognition test. Another nine performed normally in the tests, yet they too had difficulty recognising faces.
The remaining 17 — including nine who married into the family — performed normally in the tests and had no difficulty recognising faces.
By charting the family tree, the researchers inferred that a great-grandparent of the eldest generation must have carried the mutation. The eldest members then passed on the mutation to their affected children and grandchildren.
Examining the genome of the affected family members revealed they had all inherited the same genome segment in one copy of their chromosome no. 15. Recall that we inherit two copies of each chromosome, one from each parent, and in this way each one of us possesses 23 pairs of chromosomes.
By sequencing the genomic DNA, the researchers found that the MCTP2 gene, located in this segment, had been altered by a mutation. As a result, one amino acid in the protein encoded by the MCTP2 gene had been replaced by another. The researchers didn’t find this mutation in any of the hundreds of thousands of human genome sequences stored on different databases.
That is, the mutation was novel and private to this family.
Validation from population studies
But how did the researchers conclude that face blindness was caused by precisely this mutation, and not by some other mutation in the candidate genome segment?
They came to their conclusion on the basis of a population screen. The researchers recruited a cohort of 2,904 individuals (743 male and 2161 female, all around 19 years of age) to answer an online questionnaire. The questionnaire incorporated elements of the face recognition test. Seventy-eight individuals scored very poorly: that is, their scores deviated by two standard deviations or more from the average score.
The researchers sequenced the genome of 75 of the poor scorers and found seven of them carried one of five other sequence alterations in the MCTP2 gene. This demonstrated that unrelated individuals who performed very poorly in face recognition tests were more likely to carry independent mutations in the MCTP2 gene compared to the general population.
Additionally, the team found that the individuals’ first-degree relatives, such as a parent, a child or a sibling, who shared their mutation also shared the facial recognition impairment.
These findings implicated the MCTP2 gene in face recognition.
As for the 68 others who did poorly on the test but had non-mutated MCTP2 genes: some of them might have had mutations in yet other genes for face recognition. Others might have suffered face recognition problems because of infection or injury. And still others might indeed have been false positives.
A questionnaire-based screen is unlikely to have been 100% specific for identifying individuals with face recognition deficits; for extraneous reasons, even ‘normal’ face recognisers might perform poorly on a questionnaire.
In the brain, the right middle fusiform gyrus, a.k.a. the fusiform face area (rFFA), is activated during facial recognition. When the researchers used functional magnetic resonance imaging to study individuals carrying the different MCTP2 mutations, they found abnormal responses in the rFFA.
When a glove becomes a puzzle
It is perplexing for most of us to imagine what it is to live with a visual agnosia. In his bestselling 1985 book ‘The Man Who Mistook His Wife for a Hat’, the gifted neurologist and writer Oliver Sacks (1933-2015) recounted case histories of some of his patients. Dr P. was a distinguished musician and teacher, and had a visual agnosia caused by a tumour in the brain.
When Dr P. was offered a glove and asked what it was, he described it as “a continuous surface infolded on itself, (with) five outpouchings…” He imagined it to be a change purse for coins. When asked to put on his shoe, he was unable to tell his foot from his shoe. He mistook water hydrants and parking metres on the street for children and patted them on the head. And he mistook his wife for a hat.
Baffled, Dr. Sacks wondered how a man such as this could function as a teacher at the Music School. Yet Dr P. taught music until the last days of his life.
With the discovery of MCTP2’s role, our helpless bewilderment regarding visual agnosia should give way to our first molecular glimpse of what actually might be happening in the troubled brain. Both Dr. Sacks and Dr P. would have been pleased with this progress.
D.P. Kasbekar is a retired scientist.
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