Two groups of researchers have shown that variants in the gene CECR1, which encodes for ADA2, are associated with blood vessel disorders.
One group found that mutations in CECR1 are associated with an ADA2 deficiency syndrome that is characterized by early onset, recurrent strokes and systemic vasculopathy.
The other group discovered that variants in CECR1 can cause polyarteritis nodosa vasculopathy.
Results of both studies appear in NEJM.
ADA2 deficiency syndrome
In the first study, Qing Zhou, PhD, of the National Human Genome Research Institute (NHGRI), and his colleagues used whole-exome sequencing to gain insight into the aforementioned syndrome, which was characterized by early onset lacunar strokes, systemic vasculopathy, and other symptoms.
The researchers performed whole-exome sequencing in 3 patients with the syndrome and their unaffected parents. In comparing 2 of the patients’ exomes to the exomes of their parents, the researchers located 2 variants in CECR1.
Sequencing a third patient revealed another harmful variant of CECR1, in addition to a small genomic deletion that shuts down the second copy of the gene.
The researchers needed only a sequence reading of that single gene to confirm that 3 other patients were affected by variants in CECR1. In all, these 6 patients were compound heterozygous for 8 mutations in CECR1.
The team discovered that these CECR1 mutations lead to the elimination of ADA2, which produces abnormalities and inflammation in blood vessel walls that ultimately result in the syndrome. So the team called the syndrome deficiency of ADA2 (DADA2).
To gain more insight into DADA2, the researchers induced ADA2 deficiency in a zebrafish model. They found that zebrafish embryos that produce less ADA2 than normal embryos have cerebral bleeds similar to those seen in some of the children with DADA2.
“Our study raises the possibility that the ADA2 pathway may contribute to susceptibility to stroke in the more general population,” said Daniel Kastner, MD, PhD, of NHGRI.
“This genome sequencing study expands what has previously been known about vascular biology. The role of ADA2 in such serious human disease is important and suggests that ADA2 variants may contribute to other, more common illnesses.”
Dr Kastner and his colleagues also sequenced the CECR1 gene in 3 patients from Turkey who had some of the symptoms of DADA2. These patients, who had polyarteritis nodosa (n=2) or small-vessel vasculitis (n=1), were homozygous for the p.Gly47Arg mutation.
ADA2 in polyarteritis nodosa
In the second study, researchers found the same mutation (p.Gly47Arg) in patients that emigrated to Israel from the country of Georgia.
“We now know that this mutation exists in the Middle East and in Pakistani populations and that it is not that uncommon,” said Ivona Aksentijevich, MD, of NHGRI. “This is the first time a single gene has been discovered that is involved in causing a system-wide form of vasculitis.”
To uncover this mutation, Paulina Navon-Elkan, MD, of the Shaare Zedek Medical Center in Jerusalem, and her colleagues sequenced 37 patients who had features of polyarteritis nodosa.
Nineteen patients were of Georgian Jewish ancestry. Sixteen of these patients came from 5 families, and 3 patients were unrelated. An additional 14 unrelated patients were of Turkish ancestry. And 4 German patients came from the same family.
The researchers found that, in all the families, vasculitis was a result of recessive mutations in CECR1.
All of the Georgian Jewish patients were homozygous for the p.Gly47Arg mutation. The German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations. And 1 Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations.
The researchers also analyzed serum specimens from the patients and found their ADA2 activity was significantly reduced.
Taking these results together, the team concluded that mutations in CECR1 cause loss of ADA2 function that can result in polyarteritis nodosa vasculopathy with a highly varied clinical expression.
