Edward S. Stenroos

Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23

Parkinsons disease (PD) is the second most common neurodegenerative disorder after Alzheimers disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.

Ataxin-3 Interactions with Rad23 and Valosin-Containing Protein and Its Associations with Ubiquitin Chains and the Proteasome Are Consistent with a Role in Ubiquitin-Mediated Proteolysis

ABSTRACT Machado-Joseph disease is caused by an expansion of a trinucleotide CAG repeat in the gene encoding the protein ataxin-3. We investigated if ataxin-3 was a proteasome-associated factor that recognized ubiquitinated substrates based on the rationale that (i) it is present with proteasome subunits and ubiquitin in cellular inclusions, (ii) it interacts with human Rad23, a protein that may translocate proteolytic substrates to the proteasome, and (iii) it shares regions of sequence similarity with the proteasome subunit S5a, which can recognize multiubiquitinated proteins. We report that ataxin-3 interacts with ubiquitinated proteins, can bind the proteasome, and, when the gene harbors an expanded repeat length, can interfere with the degradation of a well-characterized test substrate. Additionally, ataxin-3 associates with the ubiquitin- and proteasome-binding factors Rad23 and valosin-containing protein (VCP/p97), findings that support the hypothesis that ataxin-3 is a proteasome-associated factor that mediates the degradation of ubiquitinated proteins.

New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): A risk factor for spina bifida acting in mothers during pregnancy?

Up to 72% of spina bifida cystica (SB) is preventable by maternal periconceptual folic acid supplementation. The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene and some other functional polymorphisms are risk factors for SB in some populations. However, despite extensive study, the genetic risk factors for SB are incompletely understood. Polymorphic alleles that diminish bioavailability of reduced folate in the mother during pregnancy could contribute to SB in her fetus, acting in the mother as teratogenic alleles. We recently discovered a polymorphic 19 bp deletion allele (frequency 0.45) within intron‐1 of dihydrofolate reductase (DHFR) that is a good candidate for such a genetic factor. Since there is precedence for intron‐1 regulatory elements and the deletion allele removes a potential Sp1 transcription factor binding site, we hypothesized that the deletion allele could be functional and act in SB mothers to increase the risk of SB in her fetus. We found that homozygosity for this deletion allele was significantly more frequent in SB mothers, but not in SB fathers or patients, compared with controls and was associated with a significantly increased odds ratio (OR) (2.035) of being an SB mother compared with other genotypes. Genotype distribution obeyed the constraints of Hardy–Weinberg equilibrium in controls, SB patients and fathers, but not in SB mothers. If confirmed, these findings could lead to improved forms of folate supplementation for pregnancy. About half of dietary folates and all of folic acid supplements must be reduced by DHFR to be available for mother and fetus. Reduced folates could be preferable for supplements during pregnancy to prevent SB.

Risk of Autistic Disorder in Affected Offspring of Mothers With a Glutathione S-Transferase P1 Haplotype

OBJECTIVES To delineate the natural history of pityriasis rosea in black children and to compare our findings with those of the American, European, and African literature on pityriasis rosea. Textbook and journal article descriptions of pityriasis rosea usually offer information about the presentation and clinical course of this condition in white patients. DESIGN Prospective observational study. SETTING The general pediatric clinic, adolescent clinic, and emergency department of Childrens Hospital of Michigan, Detroit, from June 2003 through May 2005. PATIENTS We followed up 50 black children with pityriasis rosea from the time of diagnosis through follow-up visits at 1, 2, and 4 weeks. Detailed observations were made and digital photographs taken at each visit. MAIN OUTCOME MEASURES Duration of illness and pigmentary sequelae. RESULTS Similarities with the medical literature were found regarding season of onset and prevalence of pruritus and of a herald patch. Our patients had more frequent facial involvement (30%) and more scalp lesions (8%) than usually described in white populations. One third had papular lesions. The disease resolved in nearly one half of patients within 2 weeks. Residual hyperpigmentation was seen in 48% of patients. Hypopigmentation developed in 29% of patients with purely papular or papulovesicular lesions. CONCLUSIONS Pityriasis rosea in black children differs in several ways from textbook descriptions. Physicians may use this information to better counsel patients about the course and potential sequelae of this condition.

Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism

BackgroundCertain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus.ResultsA likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearsons chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism.ConclusionAlthough the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.

The tau A0 allele in Parkinson's disease.

Parkinsons disease (PD) is primarily an α‐synucle‐ inopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta‐analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta‐analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy‐Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis.

Genetic variant of glutathione peroxidase 1 in autism

Genetic factors can contribute to autistic disorder (AD). Abnormal genes of oxidative stress pathways and increased oxidative stress have been reported in autism spectrum disorders. Polymorphisms of genes involved in glutathione metabolism, e.g. GSTP1 and GSTM1 are reportedly associated with autistic disorder. We investigated a GCG repeat polymorphism of a human glutathione peroxidase (GPX1) polyalanine repeat (ALA5, ALA6 and ALA7) in 103 trios of AD (probands and parents) using the transmission disequilibrium test. Significant transmission disequilibrium (p=0.044) was found in the overall transmission of the three alleles. The ALA6 allele was under transmitted (p=0.017). These results suggest that possessing this ALA6 allele may be protective for AD. Future study of interaction of the GPX1 GCG repeat and other gene polymorphisms such as the MnSOD ALA16 or the GPX1 Pro198Leu polymorphism in this cohort of AD families may shed light in whether the combination of the ALA6 allele with another polymorphism of antioxidant allele contributes to the increased oxidative stress in autism.

HLA-DR4 as a Risk Allele for Autism Acting in Mothers of Probands Possibly During Pregnancy

OBJECTIVES To test whether HLA-DR4 acts in the mother, possibly during pregnancy, to contribute to the phenotype of autistic disorder in her fetus. DESIGN Transmission disequilibrium testing in case mothers and maternal grandparents. SETTING Previous studies have consistently shown increased frequency of HLA-DR4 in probands with autism and their mothers, but not their fathers. However, this has been documented only in case-control studies and not by a more direct study design to determine whether HLA-DR4 acts in mothers during pregnancy to contribute to autism in their affected offspring. PARTICIPANTS We genotyped for HLA-DR alleles in members of 31 families with parents and maternal grandparents. Probands with autism were tested using the Autism Diagnostic Observation Schedule-Western Psychological Services and Autism Diagnostic Interview, Revised. There was 80% power to detect an odds ratio of 3.6. Participants were all families from New Jersey and were similar in number to earlier studies of autism and HLA-DR4. OUTCOME MEASURES Analysis was by standard transmission disequilibrium testing. As a secondary test we examined the possibility of maternal imprinting. RESULTS Significant transmission disequilibrium for HLA-DR4 was seen (odds ratio, 4.67; 95% confidence interval, 1.34-16.24; P = .008) for transmissions from maternal grandparents to mothers of probands, supporting a role for HLA-DR4 as an autism risk factor acting in mothers during pregnancy. Transmission disequilibrium was not seen for HLA-DR4 transmissions from parents to probands or from mothers to probands. CONCLUSIONS The HLA-DR4 gene may act in mothers of children with autism during pregnancy to contribute to autism in their offspring. Further studies are required to confirm these findings.

Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found.

Teratogenic Alleles in Autism and Other Neurodevelopmental Disorders

Genes for neurodevelopmental disorders have proven difficult to find. In the case of autism, even though a number of genes associated with the disorder have been identified, the cause of the disorder is far from clear. We discuss here a new category of genetic contribution to human disorders, i.e., gene variants (alleles) that act in mothers during pregnancy to contribute to the neurodevelopmental disorder in her offspring. We have termed these maternally acting alleles “teratogenic alleles” because they act in the fetus in a way somewhat analogous to chemical teratogens or drug teratogens ingested by a mother during pregnancy that act to damage her fetus. Although two examples of this mechanism have been known for some time, new examples have been found and since 2003 the number of examples has more than doubled. Even though this number is growing rapidly, the present number, 33, is not large. It is not clear whether this is so because teratogenic alleles are not yet well known and therefore not looked for, whether the possibility of a teratogenic allele is not considered when studies are designed, or whether there are in fact very few teratogenic alleles in comparison with alleles that act in the fetus. All of the teratogenic alleles reported so far have been in neurodevelopmental and developmental disorders. Again it is not clear whether this is simply because these are the disorders that happen to have been studied so far by suitable study designs, or whether teratogenic alleles are actually more commonly encountered in these disorders, perhaps as a regular feature or even as a characteristic feature of these disorders.