Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.
The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.
Gerstmann-Sträussler-Scheinker disease (GSS) is caused by several different point mutations of the prion protein (PrP) gene, each of which generally produces a distinct clinical phenotype. An ataxic form of GSS is genetically linked to a mutation at codon 102 (CCG-->CTG) leading to the substitution of leucine for proline, while a "telencephalic" variant of GSS, in which dementia is the predominant symptom and ataxia is minimal, has been described in two kindreds with a mutation at codon 117 (GCA-->GTG) resulting in the substitution of valine for alanine. In this report, we present a family with ataxic GSS that has, however, the same mutation at codon 117 as is present in the telencephalic variant of GSS. Other than an additional silent mutation (GCA-->GCG) at codon 117 on the normal allele, there were no other mutations detected. At the polymorphic codon 129, valine was encoded by both alleles in the proband that we studied. Why this family with prion disease (PrP-A117V) should present with ataxia instead of dementia, which was found in two previously identified families with the same PrP gene mutation, remains to be established.
Expression of the E6 and E7 genes of human papillomavirus (HPV) type 16 have been implicated in the etiology of anogenital premalignant and malignant lesions. To evaluate whether variations in the HPV-16 E6 sequence were related to the incidence of high-grade anal neoplasia, 628 HPV-16-positive anal specimens from 193 human immunodeficiency virus (HIV)-positive and 59 HIV-negative participants were typed for variations in 15 E6 nucleotide positions. Although most participants were infected with a prototype strain, 15 (6%) carried the G131 variant, and 12 (5%) were infected with the Af1a variant. Two new variants not previously reported were identified as well. An elevated risk for high-grade anal squamous intraepithelial lesions was associated with infection by G131 variants, compared with the prototype strain (odds ratio, 3.4; 95% confidence interval, 1.1-10), after controlling for HIV status. These data provide further evidence for HPV strain variation as a factor in determining the natural history of anogenital neoplasia.
Highly oncogenic human papillomavirus (HPV) 16 and 18 variants might be expected to be particularly aggressive in HIV-positive women. The association of HPV16 and 18 variant lineages with race, human immunodeficiency virus (HIV) coinfection, CD4+ T-cell count, HIV-RNA level, time-to-clearance of HPV infection and presence of squamous intraepithelial lesions (SIL) among women in the Women's Interagency HIV Study was studied. Subjects were followed semi-annually with Pap smear and cervicovaginal lavage (CVL). HPV DNA was detected in CVLs using MY09/11 L1 PCR assay. Specimens positive for HPV16/18 underwent E6 PCR and sequencing to determine the variant present. Specimens from 195 HPV16-and 162 HPV18-positive women were classified into variant lineages based on sequencing results. African variants of HPV16 and HPV18 were significantly more prevalent among African-Americans than among Caucasians [42 versus 14 % (P=0?001) and 60 versus 13 % (P<0?001), respectively]. However, it was not possible to detect associations between the HPV16 or 18 variant lineages and other factors studied. African variants of HPV16/18 were more common in women of African descent living outside Africa, which could reflect mixing behaviours and/or immunogenetic factors. However, in a large population of HIV-infected women, the variant of HPV16 or 18 was unrelated to persistence of infection or presence of SIL. If non-European variants are more oncogenic, the effect may involve a late stage in cervical tumorigenesis. INTRODUCTIONEstablishment of a persistent infection by oncogenic human papillomavirus (HPV) is thought to be central to the development of most cases of cervical cancer. Over 95 % of cervical tumour specimens harbour HPV DNA. However, HPV types (defined by their genotypes) vary greatly in the strength of their association with cervical cancer. Of the more than 90 HPV types that have been officially classified, more than 40 commonly infect cervical epithelial cells, but only a subset of these cervical HPVs, termed high-risk or oncogenic HPV types, account for almost all cervical cancers. Two HPV types, HPV16 and 18, alone account for approximately 50 and 14 % of cervical cancers, respectively (Bosch et al., 1995;Walboomers et al., 1999). These two HPV types can be further categorized by genotype to identify intra-type variants that may have different oncogenic risks (Londesborough et al., 1996).Several epidemiological studies have found that certain HPV16 and 18 variants may be more strongly associated with cervical cancer (Burk et al., 2003;Hildesheim et al., 2001;Ho et al., 1993;Londesborough et al., 1996;Nindl et al., 1999;Villa et al., 2000;Xi et al., 1995Xi et al., , 1997Zehbe et al., 1998Zehbe et al., , 2001b. By convention, variants are defined as HPVs that differ by <5 % of the nucleotide sequence in non-coding regions and <2 % of nucleotides in coding regions (Bernard et al., 1994). HPVs with genotype differences greater than this are considered to be different HPV types. HPV16 and 18 variants are typically classified int...
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