A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers

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Abstract

A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations; however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.

Research Highlights

► An adult-onset neuronal ceroid lipofuscinosis (NCL) occurs in Tibetan terriers. ► Tibetan terrier NCL was mapped to the telomeric region of canine chromosome 2. ► A deletion and frame shift in ATP13A2 causes Tibetan terrier NCL ► Human ATP13A2 mutations are not common causes of Kufs disease (adult-onset NCL).

Introduction

The neuronal ceroid lipofuscinoses (NCLs) are a group of progressive, neurodegenerative diseases characterized by the accumulation of a variety of autofluorescent proteinaceous materials within lysosomes in the brain, retina and other tissues. Homozygous mutations which severely curtail the function of at least eight different human genes have been reported to cause NCLs in infants and children (Jalanko and Braulke, 2009). Other mutations in some of these same genes produce proteins with residual biological activities, which can delay the onset of clinical signs until adulthood (van Diggelen et al., 2001). The genetic etiologies are as yet unknown for a second diverse set of adult-onset NCLs collectively referred to as Kufs disease.

NCLs have been found or induced in a variety of domestic and laboratory animals (Jalanko and Braulke, 2009, Jolly, 1995, Katz et al., 2001). Mutations in CLN1, CLN2, CLN5 and CLN8 cause early-onset canine NCLs (Awano et al., 2006a, Katz et al., 2005a, Melville et al., 2005, Sanders et al., 2010). Adult-onset NCL families have been reported in several dog breeds (Alroy et al., 1992, Evans et al., 2005, Narfstrom et al., 2007, Riis et al., 1992, Siso et al., 2004). The adult onset NCL of American Bulldogs is caused by a mutation in CTSD (also known as CLN10) which encodes cathepsin D with residual protease activity (Awano et al., 2006b). The recent discovery of an ARSG mutation in American Staffordshire terriers with adult-onset NCL has resulted in the nomination of human ARSG as a potential Kufs disease locus (Abitbol et al., 2010). The disease in American Staffordshire terriers differs from most other NCLs in that the autofluorescent inclusions were found primarily in the thalamus and cerebellum (Siso et al., 2004); whereas, the autofluorescent inclusions are typically distributed throughout the brain in Kufs disease and other types of NCL (Berkovic et al., 1988, Jalanko and Braulke, 2009). A wide-spread distribution of autofluorescent inclusions occurs in the brains of Tibetan terriers with adult-onset NCL (Alroy et al., 1992, Katz et al., 2005b, Katz et al., 2007, Riis et al., 1992) and this disease has been proposed to be a Kufs disease model (Abitbol et al., 2010, Katz et al., 2005b, Katz et al., 2007, Riis et al., 1992, Shibuya et al., 1998).

ATP13A2 is a member of the superfamily of P-type ATPase genes which encode a wide variety of ion pumps (Thever and Saier, 2009). Here we describe experiments indicating that homozygosity for a truncating mutation in ATP13A2 causes adult-onset NCL in Tibetan terriers. Homozygous truncating mutations in human ATP13A2 cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease not currently recognized as an NCL (Ramirez et al., 2006). The KRS locus is also known as PARK9 because l-dopa responsive parkinsonism is a prominent early clinical feature of KRS (Lees and Singleton, 2007); however, Tibetan terriers with NCL do not show signs of parkinsonism. The clinical features of the human and canine ATP13A2-deficiency diseases are compared in this report. Also reported are the results from the resequencing of ATP13A2 from 28 Kufs disease patients.

Section snippets

Materials and methods

Previously described methods were used to isolate DNA from 439 Tibetan terriers (Katz et al., 2005a). For 57 of these dogs, a presumptive diagnosis of NCL was based on the owner's responses to a questionnaire about abnormal behavioral signs (Katz et al., 2005b). Thirty-six of the Tibetan terriers with a presumptive diagnosis of NCL were euthanized at the owner's request and tissues from the brains and eyes were prepared for electron and fluorescence microscopy as previously described (Awano et

Results

Of the 439 Tibetan terriers represented in our DNA collection, 57 exhibited behavioral changes and ataxia consistent with NCL. Cerebral, cerebellar and occular tissue samples were collected at necropsy from 36 of these potentially affected dogs. The presence of autofluorescent cytoplasmic inclusions in 33 of these samples confirmed the diagnosis of NCL (Fig. 1) and excluded NCL as the cause of the neurological signs in the remaining 3 dogs. Electron microscopy revealed the presence of

Discussion

Homozygous or compound heterozygous mutations in human ATP13A2 can cause KRS (Ramirez et al., 2006). To date, only 16 KRS patients and 8 ATP13A2 KRS-causing mutations have been described (Crosiers et al., 2011, Di Fonzo et al., 2007, Ning et al., 2008, Paisán-Ruiz et al., 2010, Ramirez et al., 2006, Santoro et al., 2011). Most of these patients had an apparently healthy early childhood and began to show signs of disease between 10 and 22 years of age. Typically, signs of parkinsonism including

Acknowledgments

Support for this research was provided by the American Kennel Club Canine Health Foundation (grants 762 and 732), the Batten Disease Support and Research Association (BDSRA), and Research to Prevent Blindness, Inc. Our thanks to the many Tibetan terrier owners and their veterinarians who donated or collected tissues and blood samples from their dogs, and to the Tibetan Terrier Club of America for their cooperation in this study. Dr. Sara Mole, Dr. Katherine Sims, the BDSRA, and the Human Brain

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