Gene mutations are likely rare cause of two families’ PAH: Study

Familial PAH makes up less than 5% of all cases

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Members from two families with diagnosed or suspected pulmonary arterial hypertension (PAH) each carried two copies of mutations that map to the CAPNS1 gene and are likely rare causes of the disease, according to a study.

The study, “Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension,” was published in Genetics in Medicine Open.

PAH occurs when the pulmonary arteries, blood vessels that supply the lungs, are narrowed. When blood travels under a higher than normal pressure, it becomes more difficult for the heart to pump it to the lungs.

This can happen due to no apparent cause (idiopathic PAH) or one of several causes. When the disease is caused by gene mutations that run in a family, it’s called familial, or heritable PAH, which makes up fewer than 5% of all cases.

Heritable PAH is believed to be passed down (inherited) in an autosomal dominant manner. This means it occurs when a child inherits one copy of a mutated gene from one parent.

Researchers in Germany and the Netherlands report on cases from two families who may have inherited the disease in an autosomal recessive manner. The two families were not related. When a disease is inherited in an autosomal recessive manner, it means a child inherits one copy of a mutated gene from each parent. The parents usually don’t have the disease.

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Gene mutations in two separate families

The first family was from Tunisia. The parents, who were first cousins, had four children. Their first child died in her second year having had episodes of temporary cessation of breathing (apnea) and an enlarged heart.

The second child had similar symptoms from an early age. She received a diagnosis of PAH and died in her third year, likely due to a pulmonary hypertensive crisis, which can occur with a sudden rise in pulmonary arterial pressure.

The youngest child began to manifest symptoms of PAH at 6 months. She had seizures and apnea during the night. She also had blue-colored lips or skin (cyanosis) due to low oxygen levels in the blood.

A right heart catheterization, an invasive test that lets doctors measure blood pressure in the heart and the lungs, revealed higher than normal pressure in the pulmonary arteries. She died at 29 months from a pulmonary hypertensive crisis.

The couple had a fourth girl, who was healthy. To try and find the cause of PAH in this family, the researchers used a technique called exome sequencing to read through protein coding regions in DNA. DNA was available from two of the girls with PAH and from the healthy child.

The two girls with PAH carried two copies of a mutation in CAPNS1, a gene that provides instructions for producing a part (subunit) of a calpain protein known to be involved in PAH’s progression. Their parents and healthy sister carried only one copy of this mutation.

Calpain proteins are involved in many processes in cells and earlier work has linked the CAPNS1 gene to how PAH progresses over time.

The researchers found that cells that carried two copies of this mutation produced a shorter version of the calpain protein that was quickly degraded by the proteasome, a structure in cells that helps destroy unwanted proteins.

The second family was of Dutch origin. The parents, who were first cousins, had three children. Their first child, a boy, died at age 5. He had suspected pulmonary hypertension.

His brother was referred to a heart doctor when he was 26 due to worsening shortness of breath (dyspnea) and a rapid heart rate (tachycardia). Ultrasound and MRI revealed an enlarged heart.

A right heart catheterization revealed higher than normal pressure in the pulmonary arteries and he was diagnosed with PAH. The disease progressed despite treatment and he died when he was 42.

Exome sequencing identified a mutation in both copies of the CAPNS1 gene in the two brothers. This mutation resulted in no calpain protein being made at all. The parents carried only one copy of the mutation, but their youngest child, a healthy girl, didn’t carry any CAPNS1 gene mutation.

“Screening of this gene in patients affected by PAH, especially with suspected autosomal recessive inheritance, should be considered,” the researchers wrote, noting, however a screen of a population of more than 13,000 people, including 1,150 with a diagnosis of PAH, found no CAPNS1 mutation . This suggests it may represent “a rather rare cause” of monogenic PAH, that is, disease caused by a single gene.

A Conversation With Rare Disease Advocates