Brain iron deposition and whole-exome sequencing of non-Wilson's disease hypoceruloplasminemia in a family

Objective

Ceruloplasmin (CP), a key human ferroxidase, can maintain the iron balance in the brain, and the familial hypoceruloplasminemia might be rare. Ceruloplasmin reduction is one of the most common features in Wilson's disease. Some patients with hypoceruloplasminemia do not fulfill the criteria for the diagnosis of Wilson's disease or other known diseases. Moreover, these patients always suffer from various degrees of abnormal brain iron deposition. We sought to investigate the genetic basis of non-Wilson's disease hypoceruloplasminemia using whole-exome sequencing.

Methods

We recruited four patients with non-Wilson's disease hypoceruloplasminemia, who visited the Department of Neurology, Shanghai First People's Hospital, China from December 2010 to February 2011. Three of them were from the same pedigree, and the other patient shared no blood relation with the others. Iron deposition in the brain was assessed using quantitative susceptibility mapping and peripheral blood DNA was extracted. The part of the exons' genome were sequenced using the NimbleGen Sequence Capture Array and high-throughput sequencing technologies. Intersection analysis at the single nucleotide polymorphism (SNP) loci was carried out. The selected loci were verified with Sanger sequencing.

Results

Magnetic resonance imaging revealed that the magnetic susceptibility in the globus pallidus, which showed with a high signal intensity, was apparently higher in three patients than that in the normal controls, indicating the presence of abnormal iron deposition in the brain. The whole-exome sequencing and Sanger sequencing primarily excluded the possibility of mutations in the CP, ATP7B, and ATP7A genes that may impact ceruloplasmin levels. The four patients presented the homozygous mutation c.3611A>C in the C12orf51 gene; this was suspected to be a causative mutation after excluding SNP loci that were the same as those in the common population, as per The 1000 Genomes Project.

Conclusion

Non-Wilson's disease hypoceruloplasminemia showed varying degrees of abnormal iron deposition in the brain, and was possibly associated with the c.3611A>C mutation in C12orf51. How copper and iron regulate the levels of one another in the body is still not fully understood. The reduction of ceruloplasmin levels and brain iron deposition probably participated in the occurrence and development of neurodegenerative diseases. Following the combination of pre-existing techniques with a new generation of gene sequencing, the early diagnosis, prevention, and treatment of non-Wilson's disease hypoceruloplasminemia and other neurodegenerative diseases can be achieved.