Spinocerebellar ataxia type 17: Report of a family with reduced penetrance of an unstable Gln(49 )TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes

BACKGROUND: Spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder in man, is caused by an expanded polymorphic polyglutamine-encoding trinucleotide repeat in the gene for TATA-box binding protein (TBP), a main transcription factor. Observed pathogenic expansions ranged from 43 – 63 glutamine (Gln) codons (Gln(43–63)). Reduced penetrance is known for Gln(43–48 )alleles. In the vast majority of families with SCA17 an expanded CAG repeat interrupted by a CAA CAG CAA element is inherited stably. RESULTS: Here, we report the first pedigree with a Gln(49 )allele that is a) not interrupted, b) unstable upon transmission, and c) associated with reduced penetrance or very late age of onset. The 76-year-old father of two SCA17 patients carries the Gln(49 )TBP allele but presents without obvious neurological symptoms. His children with Gln(53 )and Gln(52 )developed ataxia at the age of 41 and 50. Haplotype analysis of this and a second family both with uninterrupted expanded and unstable pathological SCA17 alleles revealed a common core genotype not present in the interrupted expansion of an unrelated SCA17 patient. Review of the literature did not present instability in SCA17 families with expanded alleles interrupted by the CAA CAG CAA element. CONCLUSION: The presence of a Gln(49 )SCA17 allele in an asymptomatic 76-year-old male reams the discussion of reduced penetrance and genotypes producing very late disease onset. In SCA17, uninterrupted expanded alleles of TBP are associated with repeat instability and a common founder haplotype. This suggests for uninterrupted expanded alleles a mutation mechanism and some clinical genetic features distinct from those alleles interrupted by a CAA CAG CAA element

Impact of Different Trace Elements on the Growth and Proteome of Two Strains of Granulicella, Class “Acidobacteriia”

Acidobacteria represents one of the most dominant bacterial groups across diverse ecosystems. However, insight into their ecology and physiology has been hampered by difficulties in cultivating members of this phylum. Previous cultivation efforts have suggested an important role of trace elements for the proliferation of Acidobacteria, however, the impact of these metals on their growth and metabolism is not known. In order to gain insight into this relationship, we evaluated the effect of trace element solution SL10 on the growth of two strains (5B5 and WH15) of Acidobacteria belonging to the genus Granulicella and studied the proteomic responses to manganese (Mn). Granulicella species had highest growth with the addition of Mn, as well as higher tolerance to this metal compared to seven other metal salts. Variations in tolerance to metal salt concentrations suggests that Granulicella sp. strains possess different mechanisms to deal with metal ion homeostasis and stress. Furthermore, Granulicella sp. 5B5 might be more adapted to survive in an environment with higher concentration of several metal ions when compared to Granulicella sp. WH15. The proteomic profiles of both strains indicated that Mn was more important in enhancing enzymatic activity than to protein expression regulation. In the genomic analyses, we did not find the most common transcriptional regulation of Mn homeostasis, but we found candidate transporters that could be potentially involved in Mn homeostasis for Granulicella species. The presence of such transporters might be involved in tolerance to higher Mn concentrations, improving the adaptability of bacteria to metal enriched environments, such as the decaying wood-rich Mn environment from which these two Granulicella strains were isolated

Exon deletions and intragenic insertions are not rare in ataxia with oculomotor apraxia 2

<p>Abstract</p> <p>Background</p> <p>The autosomal recessively inherited ataxia with oculomotor apraxia 2 (AOA2) is a neurodegenerative disorder characterized by juvenile or adolescent age of onset, gait ataxia, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum AFP levels. AOA2 is caused by mutations within the senataxin gene (<it>SETX</it>). The majority of known mutations are nonsense, missense, and splice site mutations, as well as small deletions and insertions.</p> <p>Methods</p> <p>To detect mutations in patients showing a clinical phenotype consistent with AOA2, the coding region including splice sites of the <it>SETX </it>gene was sequenced and dosage analyses for all exons were performed on genomic DNA. The sequence of cDNA fragments of alternative transcripts isolated after RT-PCR was determined.</p> <p>Results</p> <p>Sequence analyses of the <it>SETX </it>gene in four patients revealed a heterozygous nonsense mutation or a 4 bp deletion in three cases. In another patient, PCR amplification of exon 11 to 15 dropped out. Dosage analyses and breakpoint localisation yielded a 1.3 kb LINE1 insertion in exon 12 (patient P1) and a 6.1 kb deletion between intron 11 and intron 14 (patient P2) in addition to the heterozygous nonsense mutation R1606X. Patient P3 was compound heterozygous for a 4 bp deletion in exon 10 and a 20.7 kb deletion between intron 10 and 15. This deletion was present in a homozygous state in patient P4.</p> <p>Conclusion</p> <p>Our findings indicate that gross mutations seem to be a frequent cause of AOA2 and reveal the importance of additional copy number analysis for routine diagnostics.</p

Extreme founder effect associated with oculocutaneous albinism type 1 (OCA1) on the island of Nias/Indonesia:How clinical genetics may help population genetics

The island of Nias/Indonesia shows an extremely reduced genetic diversity indicating a strong founder effect. One such disorder that can easily be ascertained during field research is albinism. All over the island, probands with albino phenotype were screened for OCA mutations. A novel homozygous tyrosinase mutation c.701C>T was identified in all four probands studied from very distinct parts of the island. The observed prevalence was 1 in 3,260. We argue that clinical genetics and mutation mapping can add to the combined power of population genetics, linguistics, and archeology for subsequent studies on the origin and migration of a given population. In our example mutation testing for tyrosinase exchange c.701C>T in probands outside Nias might be helpful in tracing the potential homelands of the Niassians. So far, candidate regions highly suggestive by population genetic and by comparative linguistic studies are Sangir Islands, Philippines and Taiwan