Mutations Newly Found in Families Link Problems with Calcium Metabolism to PF

Mutations in two genes, S100A3 and S100A13, were found to be linked to an atypical, early onset form of pulmonary fibrosis (PF) in two families in Saudi Arabia.

The newly identified gene variants add to knowledge of the underlying mechanisms of PF development, and further support the involvement of calcium metabolism in this disease.

The cases were described in the study “An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13,” which was published in the European Respiratory Journal by a team led by researchers at King Faisal Specialist Hospital and Research Centre in Riyadh.

In one of these families, three siblings — from a total of seven children born to consanguineous parents — developed PF at 12 and 13 years old. Both parents and the remaining siblings were healthy, while all three children had an identical clinical presentation of the disease, with breathing difficulties that began in their early teen years but no additional organ manifestations.

PF was confirmed by chest computed tomography (CT) imaging, and showed extensive involvement at the core of the lungs. Pulmonary function tests revealed that they had severe respiratory restriction and poor oxygen transfer.

Their respiratory symptoms worsen significantly with age, and all three children developed chronic type 2 respiratory failure — with elevated blood carbon dioxide levels — that required noninvasive ventilation. Two underwent a lung transplant, but died at 22 and 23 years old due to complications with the transplanted lungs. The third sibling died at age 23 of severe respiratory failure.

Four third-degree cousins of these siblings had a similar clinical profile. Two girls died of respiratory failure in their late 20s without any further medical characterization. The other two girls had an early onset of respiratory symptoms and signs of PF with a pattern of severe respiratory restriction, but no evidence of disease in other organs.

In a second family, researchers identified six siblings from a total of 10 children who showed a strikingly similar clinical pattern to the unrelated family.

Four of the affected children (two girls and two boys) died of lung disease between the ages of 25 and 32. The surviving sisters developed initial respiratory symptoms in their teens, which then progressed to a severe respiratory restriction pattern.

One sister underwent a lung transplant at 27, and is now 35 years old and in good health. The other is on the waiting list for a lung transplant.

Evaluation of both families failed to identify autoimmune or environmental factors that could explain their symptoms and overall disease progression.

Researchers instead suspected that these patients had a genetic form of PF.

Evaluation of 13 elements (both affected and unaffected) from the two families showed they were carriers of mutations in the S100A3 and S100A13 genes, which encode proteins that are involved in calcium metabolism and balance.

The identified mutations were found to negatively affect protein levels, leading to significantly lower calcium release in fibroblasts (connective tissue cells) of patients compared to healthy controls. Mitochondria (a cell’s energy source) in patient fibroblasts also showed structural abnormalities and impaired activity, resulting in a greater production of damaging oxidative compounds.

Overall, the study provides evidence that S100A3 and S100A13 proteins play a role in the development of an atypical form of PF characterized by early onset and respiratory constriction.

These data demonstrate that “inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins,” the researchers concluded.

Computational analysis and experimental data confirmed that co-inheritance of both S100A3 and S100A13 mutations are associated with PF, but “it remains unclear if either variant alone is sufficient to cause disease,” they added.

Data also suggested that a re-balancing of calcium metabolism (a “calcium-based therapy”) may be way an attractive way of managing or reversing PF.