TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs

Abstract

Clinical, pathological and genetic examination revealed an as yet uncharacterized juvenile-onset neuroaxonal dystrophy (NAD) in Spanish water dogs. Affected dogs presented with various neurological deficits including gait abnormalities and behavioral deficits. Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord. Iron accumulation was absent. Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry. The family history of the four affected dogs suggested an autosomal recessive inheritance. SNP genotyping showed a single genomic region of extended homozygosity of 4.5 Mb in the four cases on CFA 8. Linkage analysis revealed a maximal parametric LOD score of 2.5 at this region. By whole genome re-sequencing of one affected dog, a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W). This canine NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary spastic paraparesis (HSP). In contrast to the canine NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways. Furthermore, the canine NAD form reveals similarities to cases of human NAD defined by widespread spheroid formation without iron accumulation in the basal ganglia. Thus TECPR2 should also be considered as candidate gene for human NAD. Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways. Consequently, this report provides the first genetic characterization of juvenile canine NAD, describes the histopathological features associated with the TECPR2 mutation and provides evidence to emphasize the association between failure of autophagy and neurodegeneration.

On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation

“…Ultimately, mutations in the TECPR2 gene are involved in neuroaxonal dystrophy (NAD) in Spanish Water Dogs without brain iron accumulation. 47 This picture resembles to that caused by PLA2G6 mutations. So far, in humans, pathogenic variants have been associated with HSP type 49, 48 with a hereditary sensory-autonomic neuropathy 49 and with a progressive motor neuron disease.…”

Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

“…Although they all share a characteristic pathological feature, i . e ., “spheroids” in the central and, rarely, peripheral nervous system, there is some variation in the onset of clinical symptoms and lesion distribution between and also within species [20]. Human infantile neuroaxonal dystrophy (INAD; OMIM 256600) or neurodegeneration with brain iron accumulation (NBIA) 2A, is one of the most common types of human NAD [7], while other types of NBIAs, such as pantothenate kinase-associated neurodegeneration (PKAN or NBIA1; OMIM 234200), mitochondrial membrane protein-associated neurodegeneration (MPAN or NBIA4; OMIM 614298), and β-propeller protein-associated neurodegeneration (BPAN or NBIA5; OMIM 300894) also represent histological hallmarks of NAD.…”

“…In dogs, NAD has previously been reported in several breeds, such as Rottweilers [9–11], Collie sheepdogs [12], Papillons [13–16], Giant Schnauzer-Beagle crossbreeds [18], Jack Russell terriers [19], Spanish Water dogs [20], and a Dachshund-cross dog [21]. Among these, genetic studies have been extensively performed for a few breeds, and only two forms of canine NAD have been characterized at the molecular level: a mitofusin 2 (MFN2) missense mutation with foetal onset NAD in laboratory dogs [18] (Giant Schnauzer-Beagle crossbreed) and a TECPR2 missense mutation in Spanish Water dogs [20].…”

“…Among these, genetic studies have been extensively performed for a few breeds, and only two forms of canine NAD have been characterized at the molecular level: a mitofusin 2 (MFN2) missense mutation with foetal onset NAD in laboratory dogs [18] (Giant Schnauzer-Beagle crossbreed) and a TECPR2 missense mutation in Spanish Water dogs [20]. However, the causal mutations of the other forms of canine NAD remain unclear.…”

TECPR2 a positive regulator of autophagy is implicated in healthy brain ageing

“…Mutations in TECPR2 have been also recently found to cause a subtype of familial dysautonomia comparable to hereditary sensory autonomic neuropathy with intellectual disability 35 . TECPR2 is also a possible candidate gene for human neuroaxonal dystrophies (NAD), which may be associated with aging and supplementary to numerous metabolic-toxic conditions 36 .…”