Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.      

A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects

We analysed a Dutch family with autosomal dominant non-syndromic progressive sensorineural hearing loss and mapped the underlying gene defect by genetic linkage analysis to a 11.0 cM region overlapping the DFNA9 interval on chromosome 14q12-q13. Clinically, the Dutch family differs from the original DFNA9 family by a later age at onset and a more clearly established vestibular impairment. A gene that is highly and specifically expressed in the human fetal cochlea and vestibule, COCH (previously described as Coch5B2 ), was mapped to the DFNA9 critical region. Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals. The same mutation was also identified in three apparently unrelated families with a similar phenotype, suggesting the presence of a Dutch founder mutation. The function of COCH is unknown but several characteristics of the protein point to a structural role in the extracellular matrix. The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins.      

Inclusion of patients with comorbidity and comedication in premarketing trials of cardiovascular drugs

Phase III trials from registration files of cardiovascular drugs were analyzed to study the inclusion of patients with concomitant morbidity and medication. For this purpose, 15 drugs were selected which were registered in the Netherlands during the period 1985–1994 for the indications hypertension, angina pectoris, hypercholesterolemia, or myocardial infarction. The results show that preregistration trials are performed in populations which present with comorbidity and comedication. Cardiovascular, endocrine, and metabolic diseases were the most prevalent coexisting diseases. Large variation was found between registration files in the reporting of data and in patterns of comorbidity. Differences in mean comorbidity and comedication per patient were found between trials performed in different regions. The impact of various definitions of patient selection criteria on the actual inclusion of patients with coexisting morbidity was analyzed. Differences in definitions resulted in different levels of inclusion. Also, trials were found to include patients when this was not allowed and vice versa. The results are discussed in relation to the question of whether the generalizability of preregistration trials can be enhanced by further utilization of data from these heterogeneous populations. The issue to study is variability between safety and efficacy in patient groups with different patterns of comorbidity and comedication. In order to allow registration authorities to consider patterns of comorbidity and comedication during the evaluation of registration files, development of guidelines for uniform reporting of data in preregistration trials is recommended. Drug Dev. Res. 51:159–168, 2000. © 2001 Wiley‐Liss, Inc.     

Is breast feeding a risk factor for eczema during the first year of life?

Breast feeding (BF) provides many advantages to the offspring; however, at present there is an ongoing debate as to whether or not it prevents allergic diseases. The aim of the current study was to investigate the effect of duration of BF on eczema in the first year of life. A birth cohort of 1128 infants was followed prospectively from 5 months of pregnancy. Data were collected using questionnaires, a medical examination and blood tests for allergy at the age of 1 yr. Breast feeding was not statistically significant associated with eczema in the first year of life [adj ORs with 95% CIs: 0.8 (0.4-1.3), 0.8 (0.5-1.3) and 1.0 (0.6-1.5) for BF duration of 1-6 wk, 7-12 wk and > or = 13 wk, respectively]. Eczema was positively associated with atopy and educational level of the mother, use of antibiotics in pregnancy and passive smoking by the child during the first 12 months. Regular postnatal contact of the infants with dogs was inversely associated with eczema. Breast feeding was positively associated with eczema among children with non-atopic parents [adj ORs with 95% CIs: 2.1 (0.4-10.6), 2.2 (0.4-11.3) and 1.9 (0.4-8.5) for BF duration of 1-6 wk, 7-12 wk and > or = 13 wk, respectively], whereas an inverse association was found among children with atopic parents [adj ORs with 95% CIs: 0.6 (0.3-1.3), 0.7 (0.3-1.4) and 0.9 (0.5-1.7) for the same BF durations]. However, these associations were not statistically significant. Breast feeding has no significant effect on the prevalence of eczema in the first year of life. The effect of BF on eczema in children depends on parental atopy.     

A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection

Background

Schistosoma mansoni and Plasmodium falciparum are common infections of school aged children in Kenya. They both cause enlargement of the spleen, but their relative contribution to the condition of splenomegaly remains unknown in areas where both infections are endemic. Here, we have investigated whether relatively high exposure to both infections has a clinically measurable effect on this condition.

Methods

96 children aged 6–16 years living along a ten kilometre stretch and within 4 km south of a river that is a source of both S. mansoni and malaria infections were examined clinically for splenomegaly along the mid clavicular line (MCL) and mid axillary line (MAL). The survey was conducted outside the malaria transmission season. The consistency of the organ was recorded as soft, firm or hard. Mapping of the locations of houses and the course of the river was undertaken. Egg counts were mapped at the household level, as were IgG3 responses to Plasmodium falciparum schizont antigen (anti-Pfs IgG3), in order to identify areas with relatively high exposure to both infections, either infection or neither infection. ANOVA was used to test for differences in egg counts, IgG3 levels and the magnitude of spleen enlargement between these areas.

Results

4 contiguous sectors were identified, one where anti-Pfs IgG3 responses and S. mansoni egg counts were both high, one where only anti-Pfs IgG3 responses were high, one where only egg counts were high, and one where both anti-Pfs IgG3 responses and egg counts were low. Spleen MAL and MCL values were significantly higher amongst children from the sector with highest IgG3 levels and highest egg counts but similar amongst children from elsewhere. Both egg counts and anti-Pfs IgG3 responses were significantly higher in children with MAL values >=4 cm. Hardening of spleens was associated with proximity of domicile to the river.

Conclusions

Micro-geographical variation in exposure to S. mansoni and malaria infections can be exploited to investigate the chronic impact of these two infections. These results provide firm evidence that relatively high exposure to both infections exacerbates splenomegaly even outside the malaria transmission season. Major implications include assessing the burden of infection in school age-children.