Rapid detection of three large novel deletions of the aspartoacylase gene in non-Jewish patients with Canavan disease.
ABSTRACT Canavan disease (CD), an autosomal recessive neurodegenerative disorder, is caused by mutations in the aspartoacylase (ASPA) gene. In the present study, the ASPA gene was analyzed in 24 non-Jewish patients with CD from 23 unrelated families. Within this cohort, we found three large novel deletions of approximate 92, 56, and 12.13 kb in length, using both self-ligation of restriction endonuclease-digested DNA fragments with long-distance inverse PCR and multiplex dosage quantitative PCR analysis of genomic DNA. The 92 kb large deletion results in complete absence of the ASPA gene in one homozygous and one compound heterozygous patient, respectively. The 56 kb large deletion causes absence of the majority of the ASPA gene except for exon 1 alone in a compound heterozygous patient. The 12.13 kb deletion involves deletion of the ASPA gene from intron 3 to intron 5 including exons 4 and 5 (I3 to E4E5I5) in a compound heterozygous patient. Patients with the three large deletions clinically manifested severe symptoms at birth, including seizures. Our study showed that the combined use of long-distance inverse PCR and multiplex dosage quantitative PCR analysis of genomic DNA is a helpful and rapid technique to search for large deletions, particularly for detection of large deletions in compound heterozygous patients.
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ABSTRACT: Canavan disease is a severe autosomal recessive leukodystrophy characterized by macrocephaly, ataxia, severe motor and mental retardation, dysmyelination, and progressive spongial atrophy of the brain. The human aspartoacylase (ASPA) gene, which catalyzes the deacetylation of N-acetyl-L-aspartate, is mutated in Canavan disease. In the presented family sequencing analysis for the aspartoacylase gene was performed on the blood samples of the parents as the affected child had died due to Canavan disease. After the mutation was detected, prenatal diagnosis was also performed and heterozygous Y88X mutation was detected in the fetus. In this report, we present a novel mutation Y88X within the aspartoacylase gene in a consanguineous family with an affected child diagnosed as Canavan disease.Fetal and pediatric pathology 04/2012; 31(4):236-9. · 0.40 Impact Factor
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ABSTRACT: The tremor rat is an autosomal recessive mutant exhibiting sterility with gonadal hypoplasia in both sexes. The causative mutation tremor (tm) is known as a genomic deletion spanning >200 kb in Chr 10q24. Spermatogenesis associated 22 (Spata22) has been shown to be a vertebrate-specific gene essential for the progression of meiosis through prophase I and completion of chromosome synapsis and meiotic recombination using a mouse repro42 mutant carrying an N-ethyl-N-nitrosourea (ENU)-induced nonsense mutation in Spata22. In this study, we show that Spata22 was identified as the gene responsible for the failure of gametogenesis to progress beyond meiosis I in tm homozygous rats by a transgenic rescue experiment. Meiosis was arrested during prophase I in the mutant testis. Precise mapping of the breakage point revealed that the deleted genomic region spanned approximately 240 kb and comprised at least 13 genes, including Spata22. Rat Spata22 was predominantly expressed in the testis, and its transcription increased with the first wave of spermatogenesis, as seen in the mouse ortholog. These results suggest that Spata22 may play an important role in meiotic prophase I in rats, as seen in mice, and that the tm homozygous rat may be useful for investigating the physiological function of Spata22, as an experimental system for clarifying the effect of a null mutation, and may be an animal model for studying the pathogenesis and treatment of infertility caused by impaired meiosis.Experimental Animals 01/2013; 62(3):219-27. · 1.46 Impact Factor
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ABSTRACT: Background Canavan Disease is a degenerative neurological condition resulting in a spongy deterioration of the brain. Much research has been conducted by the medical community regarding this condition, but little research can be found in the psychological literature. Method A review of the scientific literature related to Canavan Disease using the Psychinfo and PubMed databases was conducted covering a 5-year span from 2006 through 2011. Concurrently, a review of parent initiated topics found on the most popular Canavan Disease Internet discussion board was conducted for comparison purposes. Results When comparing the topics discussed and information sought among parents with the themes noted in the extant scientific literature, researchers found an exceedingly small overlap between the two communities of interest. In the scientific literature, published research on Canavan Disease focused on three areas: the biochemistry of Canavan Disease, diagnosis and genetic counselling, and clinical therapeutic approaches in Canavan Disease. Of the 42 unique topics raised on a popular Internet discussion board, however, only three (7%) fell into the category of diagnosis and genetic counselling, none (0%) fell into the category of the biochemistry of Canavan Disease, and four fell into the category of clinical therapeutic approaches in Canavan Disease (10%). Of the four posts addressing clinical therapeutic approaches to Canavan Disease, only one post truly overlapped with the topics addressed by the scientific community. Worded differently, while these three categories comprise 100% of the extant scientific literature regarding Canavan Disease, they comprise only 17% of the parent-raised topics. The remaining 83% of parent-raised topics addressed concerns not currently being focusing upon by the scientific community, namely, non-medical practical issues, information regarding specific characteristics of Canavan Disease, non-medical developmental and quality of life issues, and day-to-day developmental and medical concerns. Conclusion By comparing the extant literature on Canavan Disease with the topics of interest raised by parents and caregivers, it seems clear that there is a significant 'underlap' of topics raised by these two communities of interest, one that may reflect a lack of sensitivity on the part of the scientific community to meet the needs of this population of knowledge seekers. It is the suggestion of these authors that developmental psychology may be the appropriate scientific field within which to address this need and fill this gap in the current literature.Journal of Intellectual Disability Research 06/2012; · 2.41 Impact Factor