Localisation of a gene for mucopolysaccharidosis IIIC to the pericentromeric region of chromosome 8.

Mucopolysaccharidosis type IIIC (MPS IIIC, or Sanfilippo syndrome C) is a rare lysosomal storage disorder caused by a deficiency of acetyl-coenzyme A:alpha-glucosaminide-N-acetyltransferase. Patients develop progressive neuropsychiatric problems, mental retardation, hearing loss, and relatively minor visceral manifestations. The pattern of transmission is consistent with an autosomal recessive mode of inheritance. The aim of this study was to find a locus for MPS IIIC using a homozygosity mapping approach. A genomewide scan was performed on DNA from 27 affected individuals and 17 of their unaffected relatives. Additional patients were recruited, and DNA was obtained from a total of 44 affected individuals and 18 unaffected family members from 31 families from 10 countries. A working candidate interval was defined by looking for excess homozygosity in patients compared with their relatives. Additional markers were genotyped in regions of interest. Linkage analysis was performed to support the informal analysis. Inspection of the genomewide scan data showed apparent excess homozygosity in patients compared with their relatives for markers on chromosome 8. Additional genotyping identified 15 consecutive markers (from D8S1051 to D8S2332) in an 8.3 cM interval for which the genotypes of affected siblings were identical in state. A maximum multipoint lod score of 10.61 was found at marker D8S519. A locus for MPS IIIC maps to an 8.3 cM (16 Mbp) interval in the pericentromeric region of chromosome 8.

Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22-and identification of a shared haplotype.

North American Indian childhood cirrhosis (NAIC, or CIRH1A) is an isolated nonsyndromic form of familial cholestasis reported in Ojibway-Cree children and young adults in northwestern Quebec. The pattern of transmission is consistent with an autosomal recessive mode of inheritance. To map the NAIC locus, we performed a genomewide scan on three DNA pools of samples from 13 patients, 16 unaffected siblings, and 22 parents from five families. Analysis of 333 highly polymorphic markers revealed 3 markers with apparent excess allele sharing among affected individuals. Additional mapping identified a chromosome 16q segment shared by all affected individuals. When the program FASTLINK/LINKAGE was used and a completely penetrant autosomal recessive mode of inheritance was assumed, a maximum LOD score of 4.44 was observed for a recombination fraction of 0, with marker D16S3067. A five-marker haplotype (D16S3067, D16S752, D16S2624, D16S3025, and D16S3106) spanning 4.9 cM was shared by all patients. These results provide significant evidence of linkage for a candidate gene on chromosome 16q22.

Lung phagocyte bactericidal function in strains of mice resistant and susceptible to Pseudomonas aeruginosa.

The host response to Pseudomonas aeruginosa lung infection varies among inbred mouse strains. Mice of the BALB/c strain are resistant to P. aeruginosa lung infection, whereas mice of the DBA/2 strain are susceptible. This phenotypic variation correlates with a difference in the magnitude of the inflammatory response induced early following infection. In order to determine whether the ability of lung phagocytic cells to kill P. aeruginosa plays a role in the host response to the infection, we measured the in vitro bactericidal activity of resident and inflammatory alveolar and interstitial macrophages, using a temperature-sensitive mutant of P. aeruginosa. Lung macrophages obtained from resistant and susceptible animals displayed similar bactericidal activities, suggesting that the ability of phagocytes to kill P. aeruginosa does not play a crucial role in the outcome of infection. The bactericidal activity of lung phagocytes was also assessed in vivo following endobronchial infection with the temperature-sensitive mutant of P. aeruginosa. Resistant mice showed a rapid influx of polymorphonuclear leukocytes (PMNs) to the bronchoalveolar space which was shortly followed by an efficient clearance of the bacteria. Susceptible mice had a delay in both the inflammatory response to P. aeruginosa and the initiation of bacterial clearance. Susceptible mice have been shown to have a defect in tumor necrosis factor alpha production when infected intratracheally with P. aeruginosa. Intratracheal instillation of tumor necrosis factor alpha to susceptible mice at the time of infection significantly improved the recruitment of PMNs to the site of infection without affecting the process of bacterial clearance. Overall, these results suggest that both recruitment of a high number of PMNs to the lungs and an efficient activation process of the phagocytes are crucial for the prompt clearance of P. aeruginosa.