Absence of an Orphan Mitochondrial Protein, C19orf12, Causes a Distinct Clinical Subtype of Neurodegeneration with Brain Iron Accumulation

Abstract

The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.

Niemann-Pick’s disease type B and brain iron accumulation

“…The list of NBIAs is continuously expanding. Besides PKAN caused by mutations in the PANK2 gene, [1,2] the best characterized subtypes include MPAN with mutations/deletions in the c19orf12 gene, [7][8][9] the PLA2G6 Associated Neurodegeneration (PLAN) with mutations in the PLA2G6 gene, [10] the Coasy Protein Associated Neurodegeneration (CoPAN) with mutations in the Coasy gene, [11] and the Beta-Propeller Protein Associated Neurodegeneration (BPAN) with mutations in the WDR45 gene. [12] A shared feature of these diseases is brain iron accumulation that is likely secondary to abnormalities in lipid metabolism and autophagy.…”

“…This deletion results in an early stop codon (p. Gly69Arg fsTer10) and has been previously reported. [7][8][9] Brain magnetic resonance imaging (MRI) of the parents was subsequently ordered on a 3 Tesla Philips scanner, which revealed increased iron in the globus pallidus on T2-Fast Field Echo (FFE) scans in the 62 years old mother's but not in the 64 years old father's brain (see Figure 2). …”

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

“…Post mortem brain examination MPAn revealed ironcontaining deposits in the GP and SN, axonal spheroids, Lewy body-like inclusions and tau-positive inclusions in various regions of the brain [121]. Little is known about gene function, but it is localized predominantly in mitochondria and it is co-regulated with genes involved in fatty acid metabolism.…”

“…Genetic work-up led to identification of the new NBIA gene, C19orf12, at chromosome 19q12 [121]. (Table 2B) A deletion of eleven basepairs leading to a premature stop codon and predicted to cause early truncation of the protein was identified in the majority of patients due to a founder effect in the Polish cohort.…”

“…Hartig et al [121] recently described a cohort of Polish NBIA patients including a subgroup of 24 cases with childhood-onset dysarthria and gait difficulty, followed by the development of spastic paraparesis, extrapyramidal features (dystonia and parkinsonism), neuropathy, optic atrophy and psychiatric symptoms. Iron deposition was present in the globus pallidus and substantia nigra.…”