Clinicopathological Relationships in an Aged Case of DOORS Syndrome With a p.Arg506X Mutation in the ATP6V1B2 Gene

Abstract

DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann-Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder.

Classification of diseases with accumulation of Tau protein

“…AGD‐like pathology in DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures) syndrome [125]…”

Case Report: Exome Sequencing Identified Variants in Three Candidate Genes From Two Families With Hearing Loss, Onychodystrophy, and Epilepsy

“…In this report, the LoF variant in ATP6V1B2 is co-segregating with the four affected individuals in two unrelated families, which clearly demonstrates that the c.1516C>T allele is the genetic cause of DDOD in autosomal dominant form. Almost all previously reported cases with the c.1516C>T ( Table 1 ) are caused by de novo mutation of this allele ( Yuan et al, 2014 ; Menendez et al, 2017 ; Zadori et al, 2020 ; Beauregard-Lacroix et al, 2021 ). However, the underlying mechanism of how the c.1516C>T variant of ATP6V1B2 causes DDOD or DOORS syndrome remains unknown.…”

“…One additional single case with DDOD in different populations was also confirmed to be caused by the same variant ( Menendez et al, 2017 ). The variant was also detected in a patient with broader clinical manifestation, including deafness, onychodystrophy, osteodystrophy-related abnormalities and intellectual disability (mental retardation), or seizures (so called DOORS syndrome) ( Zadori et al, 2020 ). More recently, the same mutation was detected in nine individuals with either DDOD syndrome (two individuals) or DOORS syndrome (seven individuals) ( Beauregard-Lacroix et al, 2021 ).…”

The <em>ATP6V1B2 </em>DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice

“…These include vacuolar ATPase subunits involved in neurotransmitter recycling or vesicular release (ATP6V1B2, ATP6V1A, ATP6V0C, ATP6V0A1). Dominant variants in ATP6V1B2 [MIM 606939], encoding a vacuolar ATPase, have been associated with 3 different syndromes, namely Zimmermann-Laband syndrome type 2 (ZLS2 [MIM: 135500]) [11], congenital deafness with onychodystrophy syndrome (DDOD [MIM: 124480]) [12][13][14][15] and deafness with onychodystrophy, osteodystrophy, intellectual disability (ID) with or without seizures syndrome (DOORS [MIM: 220500]) [16]. The ATP6V1B2 nonsense variant p.R506*, generating a -6 amino acid truncated protein, causes DDOD syndrome usually without seizures [12][13][14][15]17] and DOORS usually with seizures [14,16].…”