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PubMed2004

Association and transmission analysis of the FMR1 IVS10 + 14C-T variant in autism.

Evidence from the high male to female ratio of individuals with autism as well as suggestive linkage data have implicated the possible involvement of X chromosomal loci in the aetiology of autism. Studies of the FMR1 gene on Xq27 have shown that occasionally individuals, and particularly females, with the [CGG] repeat expansion and methylation mutation may present with autistic symptoms. However, molecular studies suggest that such mutations are not a major cause of autism. Previously, we have screened autism probands for mutations in regions of the FMR1 gene downstream of the [CGG] repeat and identified an intronic variant in the FMR1 gene, IVS10 + 14C-T, which was present at a significantly higher frequency in autistic individuals compared to controls individuals. We have now investigated this variant in a further 136 autism families and 186 control individuals. We have established that the variant is significantly more frequent among East Asian individuals within our affected and control groups (P < 0.0001) and although we observed a trend of higher transmission frequency of the rare allele to affected individuals, there was no significant evidence in either family-based or case/control association studies for this variant in autism (P > 0.05).

Autistic Disorder↗
PubMed2000

Evidence for a new locus for X-linked retinitis pigmentosa (RP23).

PURPOSE: X-linked retinitis pigmentosa (XLRP) is a degenerative disease of the retina characterized in the early stages of disease by night blindness as a result of rod photoreceptor loss, progressing to severe disease with loss of central vision by the third decade in affected males. XLRP displays exceptional genetic heterogeneity, with five reported loci on the human X-chromosome. To investigate the level of heterogeneity for XLRP in the patient pool in the current study, extensive haplotype analysis, linkage analysis, and mutation screening were performed. METHODS: Haplotype analysis of a family with diagnosed XLRP was scored with more than 34 polymorphic markers spanning the entire X-chromosome, including regions already identified as harboring XLRP genes and retina-specific genes. Two-point and multipoint lod scores were calculated. Affected male DNA was amplified with primers specific for the retinoschisis gene (XLRS1), and the products were screened for nucleic acid alterations by direct automated sequencing. RESULTS: In this article haplotype and linkage data are presented identifying a new locus for XLRP on the short arm of the X-chromosome, distinct from previously reported gene localizations for XLRP. The phenotype is atypical, in that the onset of vision loss in the male members of this family is unusually early, and female obligate carriers have normal fundi and waveforms. Informative recombination events in this family define a locus for XLRP (RP23) on Xp22 between the markers DXS1223 and DXS7161, spanning approximately 15 cM. A maximum lod score of 2.1 was calculated for the locus order DXS7103-8 cM-(RP23/DXS1224)-4 cM-DXS999. This new locus (RP23) encompasses the retinoschisis disease gene; therefore, XLRS1 was screened for a mutation. No sequence alteration was identified indicating that mutations in the coding region of the gene responsible for retinoschisis do not cause RP23. CONCLUSIONS: The results describe evidence for a new locus for XLRP (RP23), adding to the established genetic heterogeneity for this disease and the number of genes expressed in ocular tissue residing on the X-chromosome.

Adult↗
PubMedDate not supplied

The effects of genotyping errors and interference on estimation of genetic distance.

Analysis of linkage data has typically been carried out assuming genotyping errors are absent. Recent studies have shown, however, that the impact of ignoring genotyping errors can be great, especially in dense marker maps [Buetow, Am J Hum Genet 1991; 49:985-994; Lincoln and Lander, Genomics 1992; 14:604-610]. Because most organisms exhibit positive chiasma interference, we use the chi 2 model [Foss et al., Genetics 1993; 144:681-691] to examine the role interference plays in the estimation of genetic distance in the presence of genotyping errors. For simplicity, we confine our analyses to samples of 1,000 fully informative gametes. Our results support previous findings that ignoring errors inflates distance estimates. The larger the error rate, the greater the inflation. For a given error rate, the relative error in estimated genetic distance is greatest when interference is known to be weak or absent. An approximation to relative error which quantifies the relation to distance, error rate, and interference is provided. Robustness of estimation to error misspecification is also investigated. When the assumed error rate is too low, distance is overestimated while interference is underestimated. The situation is reversed when too large an error rate is assumed (interference is overestimated, and distance underestimated). Unfortunately, the joint estimation of distance and interference is not very robust to error misspecification.

Genetic Linkage↗
PubMedDate not supplied

Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

Animals↗
PubMed1993

Negative-configuration electroretinogram in Oregon eye disease. Consistent phenotype in Xp21 deletion syndrome.

OBJECTIVE: To determine whether abnormal configurations on electroretinogram were a consistent finding in patients with Xp21 deletion and to characterize the associated ophthalmologic phenotype. DESIGN: Case series. SETTING: University hospitals and eye institutes. PATIENTS: Five patients with complex glycerol kinase deficiency (Duchenne-type or Becker's muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia) and demonstrated chromosomal deletions at Xp21. Control patients were matched by age. MAIN OUTCOME MEASURES: Clinical information was obtained from medical records. Complete ophthalmologic examinations were performed. Electroretinography was performed using a Ganzfeld technique and chloral hydrate sedation. RESULTS: We report the clinical features and abnormal configurations on electroretinograms of five patients with complex glycerol kinase deficiency, including follow-up studies on a previously described patient. The original patient had ocular hypopigmentation; four, strabismus; two, myopia; three, astigmatism; and one, symptomatic night blindness. All had negative configurations on scotopic electroretinograms showing a reduced-amplitude B wave in the dark-adapted state. CONCLUSIONS: Our original report suggested a diagnosis of Aland Island eye disease, which appears to be an incomplete form of congenital stationary night blindness. Linkage data place Aland Island eye disease and congenital stationary night blindness at Xp11, whereas our patients had deletions at Xp21. The phenotype reported here may represent the effects of a single gene defect or the compound effects of the Xp21 contiguous gene syndrome (complex glycerol kinase deficiency). The phenotype is referred to as Oregon eye disease.

Adolescent↗
PubMed2006

Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.

CONTEXT: Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. OBJECTIVE: To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992. MAIN OUTCOME MEASURE: Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems. RESULTS: There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41,779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100,000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100,000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P<.001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk. CONCLUSION: Elevated serum HBV DNA level (> or =10,000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.

Adult↗
PubMed1997

Clinical and locus heterogeneity in brachydactyly type C.

Brachydactyly type C is characterized by shortness of the second and fifth middle phalanges and the first metacarpal. It is inherited as an autosomal dominant trait, and is noted for its widely variable clinical phenotype both within and between families. In most families involvement is limited to the hands. However, in some families additional skeletal and non-skeletal findings have been reported. We report on 12 affected members from a 5 generation kindred that segregates a brachydactyly type C phenotype. All affected individuals had shortness principally affecting the second and fifth phalanges and first metacarpal. However, the metacarpal-phalangeal profile indicated that other digital elements were short as well. In addition, one affected individual had a bilateral Madelung deformity, but none had foot involvement. No other non-skeletal findings cosegregated with brachydactyly in this family. Recently, a gene for brachydactyly type C has been localized to 12q24. This was done by studying a large kindred first reported by Haws [1963], which manifests both hand and foot anomalies. Here we present linkage data which excludes the 12q24 locus in our kindred, indicating locus heterogeneity as one explanation for the interfamilial variability described in brachydactyly type C.

Adolescent↗
PubMed1999

Breast cancer risk among relatively young women employed in solvent-using industries.

BACKGROUND: Breast cancer is the most common tumor among women, and the causes remain almost unknown apart from changes in the reproductive pattern. Based on experimental evidence, some organic solvents may have carcinogenic properties to the female breast. METHODS: We used a comprehensive national data linkage to examine the adjusted breast cancer risk among relatively young (20-55 years) Danish women employed in industries with extensive use of organic solvents (i.e., the metal product, wood and furniture, printing, chemical, and textile and clothing industries). Relative risks (OR) were estimated from a matched case-control study on 7,802 women with breast cancer (1970-1989). Potential exposure to organic solvents was accessed from the duration of employment within the selected industries and reconstructed from the files of a nationwide compulsory pension fund. Socioeconomic status and the individual reproductive pattern were obtained from the central person registry. RESULTS: The adjusted OR for breast cancer after 15 years latency was increased in each of the selected industrial groups (from 1.4 to 2.4). For the entire group with over 10 years of employment, the OR was significantly elevated (twofold). CONCLUSIONS: This study supports the observation that long-term occupational exposure to organic solvents may play a role in breast cancer risk. However, some residual confounding may exist, and further studies are required to identify specific carcinogenic organic solvents.

Adult↗
PubMed1998

Molecular cloning, genetic mapping, and developmental expression of a bovine transforming growth factor beta (TGF-beta) type I receptor.

A full-length cDNA encoding the bovine transforming growth factor beta (TGF-beta) receptor type I (bT beta R-I) was isolated from a placenta cDNA library. The deduced protein sequence of 499 residues contains a single transmembrane domain, a cysteinerich extracellular domain, and an intracellular kinase domain with predicted serine/threonine specificity. The amino acid sequence is 96% and 95% identical with its human and mouse homologues, respectively. Genetic mapping assigned the TGFBR1 gene to bovine chromosome 8 at a male genetic distance of 2 centimorgan from D8S28. Assuming conservation of gene order, the linkage data define a breakpoint in mammalian chromosome evolution. Both TGF-beta receptor type I and II mRNAs were found to be expressed in bovine oocytes and preimplantation two-cell, four-cell, eight-cell, morula-, and blastocyst-stage embryos, as determined by heminested reverse transcription polymerase chain reaction (RT-PCR). The mRNA expression patterns of TGF-beta receptor types I, II, and III in a variety of bovine organ tissues were examined by Northern blot hybridization, and highest levels were detected in lung and ovary.

Amino Acid Sequence↗
PubMed2000

Birth defects prevalence among infants of Persian Gulf War veterans born in Hawaii, 1989-1993.

BACKGROUND: Gulf War veterans (GWVs) have expressed concern about possible teratogenic exposures. However, epidemiologic studies on birth defects prevalence among their progeny have been limited to military hospitals, anomalies diagnosed among newborns, or self-reported data. To measure the prevalence of selected birth defects among infants of GWVs and nondeployed veterans (NDVs) in Hawaii, using birth defects surveillance records. METHODS: Personal identifiers of 684,645 GWVs and 1,587,102 NDVs and their families were matched against birth certificate records of 99,545 live births reported to the State of Hawaii Department of Health between 1989 and 1993 to identify births to military personnel. These births were matched with records from the Hawaii Birth Defects Program. RESULTS: A total of 17,182 military infants (3,717 GWV infants and 13,465 NDV infants) were identified. Of these, 367 infants (2.14/100 live births) were identified with one or more of 48 major birth defects diagnoses. The prevalence of the 48 birth defects were similar for GWV and NDV infants during the prewar and postwar periods, and among GWV infants who were conceived before and after the Gulf war. CONCLUSIONS: The results must be interpreted with caution because of the small number of affected infants in each birth defects category. This study demonstrated the feasibility of measuring birth defects prevalence among military infants through multiple data linkage. Further, it included live births to parents who had separated from the military, births in civilian hospitals, and birth defects diagnosed through the first year of life.

Adult↗
PubMedDate not supplied

Linkage relationships between DXS105, DXS98, and other polymorphic DNA markers flanking the fragile X locus.

We report on linkage data between DXS105, DXS98, the locus for the fragile X syndrome (FRAXA), and 3 other polymorphic loci that flank the FRAXA locus. An analysis was undertaken to determine the relative positions of DXS105 and DXS98 and to test the assignment of DXS105 to a location proximal and closely linked to FRAXA. In this study of fragile X fra(X) syndrome families, the DXS105 locus was calculated to be proximal to FRAXA with a maximum lod score of 10.36 at theta = 0.08. DXS105 was also shown to be closely linked to the gene for factor IX (F9)(Z = 11.84 at theta = 0.08) and to DXS98 (Z = 4.91 at theta = 0.04). The order of the loci proximal to FRAXA is most likely centromere-factor IX-DXS105-DXS98-FRAXA-telomere. The use of DXS105 and DXS98 in clinical investigations should significantly increase the accuracy of risk assessment in informative fragile X families.

Chromosome Mapping↗
PubMed1992

Clinical variability and genetic heterogeneity within the Acadian Usher population.

A number of Usher syndrome (USH) families are found among the French-Acadians living in southwestern Louisiana. These families are descended from a few common ancestors, suggesting that USH may be homogeneous within this ethnic group. However, we report distinct phenotypic variability. Based on differences in psychomotor development and tests of auditory and vestibular function, Acadian individuals with both USH Type 1 and Type 2 can be identified. One additional family, with unusual findings, represents a third clinical phenotype. Linkage data strongly support these clinical observations.

Blindness↗
PubMed2004

Ethnic differences in utilization of invasive cardiac procedures and in long-term survival following acute myocardial infarction.

BACKGROUND: Ethnic differences in coronary mortality have been documented, and South Asians from the Indian subcontinent are particularly vulnerable. HYPOTHESIS: This study sought to determine whether there was a difference in the utilization of invasive cardiac procedures and long-term mortality in survivors of myocardial infarction (MI) among Chinese, Malays, and South Asians in Singapore. METHODS: All MI events in the country were identified and defined by the Singapore Myocardial Infarction Register, which uses modified procedures of the World Health Organization MONICA Project. Information on utilization of coronary angiography, coronary angioplasty, coronary artery bypass graft, and survival was obtained by data linkage with national billing and death registries. Hazard ratios (HR) were calculated using the Cox proportional hazards model with adjustment for baseline characteristics. RESULTS: From 1991 to 1999, there were 10,294 patients who survived > or = 3 days of MI. Of these, 40.6% underwent coronary angiography and 16.5% a revascularization procedure < or = 28 days. Malays received substantially less angiography (34.0%) and revascularization (11.4%) than Chinese (41.9%, 17.9%) and South Asians (40.0%, 16.3%). The ethnic disparity increased during the 1990s, particularly in the performance of coronary angiography (p = 0.038). While fatality declined during the study period for Chinese and South Asians, the rate remained stable for Malays. After a median follow-up period of 4.1 years, survival was lowest among Malays (adjusted HR, 1.28; 95% confidence interval, 1.15-1.42, compared with Chinese). CONCLUSION: Ethnic inequalities in invasive cardiac procedures exist in Singapore and were exacerbated in the 1990s. Inequalities in medical care may contribute to the poorer longterm survival among Malays.

Adult↗
PubMed2003

Prostate carcinoma risk subsequent to diagnosis of benign prostatic hyperplasia: a population-based cohort study in Sweden.

BACKGROUND: Pathologically, benign prostatic hyperplasia (BPH) is not considered a precursor for prostate carcinoma. However, because the two conditions share not only a similar hormonal environment within the prostate but also several common risk factors, it is possible that men with BPH may be at increased risk of prostate carcinoma due to these shared factors. METHODS: To elucidate this further, the authors used Swedish nationwide population-based record-linkage data to assess prostate carcinoma risk up to 26 years after the diagnosis of BPH among 86,626 men. RESULTS: Overall, relative to the general population, patients with BPH experienced little, if any, excess risk of prostate carcinoma (2% excess incidence after 10 years of follow-up). However, patients with BPH with and without surgical intervention experienced different prostate carcinoma risk patterns. Those undergoing transvesicular adenomectomy had a significant 22% lower incidence and a 23% lower mortality after the first 5 years of follow-up and those undergoing transurethral resection had a significant 10% higher incidence but a 17% lower mortality. In contrast, after the first 5 years, patients with BPH who did not receive surgical intervention experienced significant excesses of both prostate carcinoma incidence (18%) and mortality (77%). CONCLUSIONS: The differences in prostate carcinoma incidence and mortality by BPH treatment type suggest that factors related to treatment or health reasons underlying the selection of treatment influence subsequent prostate carcinoma risk. Further studies are needed to confirm the minimal excess risk of prostate carcinoma among BPH patients overall and the possible impact of BPH treatment methods on subsequent prostate carcinoma risk.

Aged↗
PubMed2001

Color bar coding the BRCA1 gene on combed DNA: a useful strategy for detecting large gene rearrangements.

Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast and ovarian cancers. BRCA1 germline mutations, however, are found less frequently than expected. Mutation detection strategies, which are generally based on the polymerase chain reaction, therefore focus on point and small gene alterations. These approaches do not allow for the detection of large gene rearrangements, which also can be involved in BRCA1 alterations. Indeed, a few of them, spread over the entire BRCA1 gene, have been detected recently by Southern blotting or transcript analysis. We have developed an alternative strategy allowing a panoramic view of the BRCA1 gene, based on dynamic molecular combing and the design of a full four-color bar code of the BRCA1 region. The strategy was tested with the study of four large BRCA1 rearrangements previously reported. In addition, when screening a series of 10 breast and ovarian cancer families negatively tested for point mutation in BRCA1/2, we found an unreported 17-kb BRCA1 duplication encompassing exons 3 to 8. The detection of rearrangements as small as 2 to 6 kb with respect to the normal size of the studied fragment is achieved when the BRCA1 region is divided into 10 fragments. In addition, as the BRCA1 bar code is a morphologic approach, the direct observation of complex and likely underreported rearrangements, such as inversions and insertions, becomes possible.

Breast Neoplasms↗
PubMed1991

Fine mapping of probes in the adenomatous polyposis coli region of chromosome 5 by in situ hybridization.

The gene for adenomatous polyposis coli has been localized to 5q21-22. We have mapped six probes from this region using isotopic or nonisotopic in situ hybridization. Using tritium-labeled probes we localized II227 (D5S37) to 5q14-15 and ECB27 (D5S98) to 5q21. Following hybridization with biotin-labeled probes, the positions of signals along the chromosomes were measured as fractional length relative to the length of the chromosome arm from centromere to qter (FLcen-qter). Ninety-five percent confidence limits, compared with standard karyotypes, provided the corresponding band localization. By this method we localized Cllpll (D5S71) to FLcen-qter 0.407-0.452 (5q21.1-21.3), ECB27 to FLcen-qter 0.426-0.473 (5q21.3), YN5.48 (D5S81) to FLcen-qter 0.459-0.496 (5q21.3-22.2), and ECB134 (D5S97) to FLcen-qter 0.509-0.533 (5q22.3-23.1). ECB220 had three sites of hybridization, a major site at FLcen-qter 0.460-0.492 (5q21.3-22.1) and minor sites at FLcen-qter 0.299-0.339 (5q14.3-15) and FLcen-qter 0.629-0.691 (5q23.3-31.2). We have shown that the chromosome 5 breakpoint in a t(5;15) translocation from a patient with Gardner's syndrome (GM03314) is between Cllpll and ECB27. Linkage data are presented suggesting that ECB27 is located on the same side of the APC locus as II227. These and published results including data on several constitutional deletions (M, SD, and brothers PW and ND) give a probable order of [cen] - [II227, proximal SD breakpoint] - [Cllpll] - [proximal PW/ND, M breakpoint(s), GM03314 breakpoint] - [ECB27] - [APC] - [YN5.48] - [distal PW/ND breakpoint] - [ECB134] - [distal M breakpoint] - [qter]. The major site of ECB220 appears to be between ECB27 and the distal PW/ND breakpoint; the distal SD breakpoint is distal to YN5.48.

Adenomatous Polyposis Coli↗
PubMed2006

Nonparametric linkage analysis using person-specific covariates.

Linkage analysis provides an important tool for mapping genes for complex disease. However its usefulness has been limited by inadequate marker density, inadequate sample sizes and the possibility that different genes account for different subtypes of the disease (phenotypic heterogeneity). The first two limitations can be addressed by high-density single nucleotide polymorphism (SNP) genotyping and the pooling of large sets of multiple-case families. Phenotypic heterogeneity can be addressed by analyses that weigh the contributions of affected family members according to characteristics of their disease phenotypes. Here we introduce a method for including such person-specific weights in nonparametric linkage analysis. We show with simulations that such weighting can provide stronger linkage signals when a causal polymorphism affects some manifestations of the disease more than others. We applied the method to prostate cancer linkage data in a region on chromosome 19p, and obtained higher lod scores by assigning weights of one to men with early-onset aggressive cancers, weights of zero to those with late-onset nonaggressive cancers, and intermediate weights to all other affected men. We have developed a modified version of GENEHUNTER that allows inclusion of person-specific weights in the nonparametric analyses. This program is freely available at http://med.stanford.edu/epidemiology/statisticalSoftware/weightedKAC.

Chromosome Mapping↗
PubMed2004

Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7).

Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [(18)F]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein.

Adult↗