Gene mutations identified in copper metabolism disorder

The finding contributes to a small but growing list of known inborn errors of copper metabolism. MEDNIK syndrome is a recently discovered disorder caused by mutations in AP1S1, a gene involved in intracellular transport of proteins including ATP7A, which plays a crucial role in regulating copper levels in the body. Copper is essential for infant growth and brain development. 

“The two mutations we have now identified in AP1B1 are very severe,” explains clinical geneticist Fowzan Alkuraya of King Faisal Specialist Hospital and Research Center in Saudi Arabia. “AP1B1 deficiency is clearly associated with copper deficiency, most likely due to impaired absorption.” 

Researchers analysed the DNA of three children from two unrelated families in the UK and Saudi Arabia with symptoms suggestive of MEDNIK, including developmental delay, deafness and skin anomalies. 

In contrast to the few patients reported so far with MEDNIK syndrome, these patients did not show evidence of copper toxicity in the liver. The difference broadens the diagnostic criteria for copper-related metabolic diseases. 

Importantly, a defect in AP1B1 “would have been skipped over” until now, says Alkuraya, “but it can be interpreted with confidence that it represents a bona fide carrier state,” meaning that genetic testing for parents carrying the mutation could help families make better-informed reproductive decisions.

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