BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) are a group of clinically and genetically heterogeneous diseases characterized by iron overload in basal ganglia and progressive neurodegeneration. Little is known about the epidemiology of NBIA disorders. In the absence of large-scale population-based studies, obtaining reliable epidemiological data requires innovative approaches. METHODS: All pathogenic variants were collected from the 13 genes associated with autosomal recessive NBIA (PLA2G6, PANK2, COASY, ATP13A2, CP, AP4M1, FA2H, CRAT, SCP2, C19orf12, DCAF17, GTPBP2, REPS1). The allele frequencies of these disease-causing variants were assessed in exome/genome collections: the Genome Aggregation Database (gnomAD) and our in-house database. Lifetime risks were calculated from the sum of allele frequencies in the respective genes under assumption of Hardy-Weinberg equilibrium. FINDINGS: The combined estimated lifetime risk of all 13 investigated NBIA disorders is 0.88 (95% confidence interval 0.70-1.10) per 100,000 based on the global gnomAD dataset (n = 282,912 alleles), 0.92 (0.65-1.29) per 100,000 in the European gnomAD dataset (n = 129,206), and 0.90 (0.48-1.62) per 100,000 in our in-house database (n = 44,324). Individually, the highest lifetime risks (>0.15 per 100,000) are found for disorders caused by variants in PLA2G6, PANK2 and COASY. INTERPRETATION: This population-genetic estimation on lifetime risks of recessive NBIA disorders reveals frequencies far exceeding previous population-based numbers. Importantly, our approach represents lifetime risks from conception, thus including prenatal deaths. Understanding the true lifetime risk of NBIA disorders is important in estimating disease burden, allocating resources and targeting specific interventions. FUNDING: This work was carried out in the framework of TIRCON ("Treat Iron-Related Childhood-Onset Neurodegeneration").

• Klíčová slova
• Autosomal recessive NBIA disorders, CoPAN, Lifetime risk, Neurodegeneration, PKAN, PLAN,
• MeSH
• databáze genetické MeSH
• dítě MeSH
• jaderné proteiny MeSH
• komplexy ubikvitinligas MeSH
• lidé MeSH
• mitochondriální proteiny genetika   MeSH
• mozek patologie   MeSH
• neuroaxonální dystrofie * epidemiologie   genetika   patologie   MeSH
• neurodegenerativní nemoci * epidemiologie   genetika   patologie   MeSH
• poruchy metabolismu železa * genetika   patologie   MeSH
• proteiny vázající vápník MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• C19orf12 protein, human MeSH Prohlížeč
• DCAF17 protein, human MeSH Prohlížeč
• jaderné proteiny MeSH
• komplexy ubikvitinligas MeSH
• mitochondriální proteiny MeSH
• proteiny vázající vápník MeSH
• REPS1 protein, human MeSH Prohlížeč

Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.

• MeSH
• fenotyp MeSH
• myši knockoutované MeSH
• myši MeSH
• transportní proteiny genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• transportní proteiny MeSH
• Wdr45 protein, mouse MeSH Prohlížeč