Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population.

The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.

Allergic rhinitis--a total genome-scan for susceptibility genes suggests a locus on chromosome 4q24-q27.

Allergic rhinitis is a common disease of complex inheritance and is characterised by mucosal inflammation caused by allergen exposure. The genetics of closely related phenotypes such as asthma, atopy and to some extend atopic dermatitis has attracted attention in recent years. Genetic reports of allergic rhinitis on the contrary have as yet been most sparse. To identify candidate regions holding genes for allergic rhinitis we performed a total genome-scan on affected sib-pair families. From 100 Danish sib-pair families selected for allergy, families containing sib-pairs matching a phenotype definition of both clinical allergic rhinitis and confirmed specific allergy were chosen. Thirty-three affected sib-pair families qualified for the scan that was undertaken using 446 microsatellite markers. Non-parametric linkage results were obtained from MAPMAKER/SIBS computer program. The study revealed one major candidate region on chromosome 4q24-q27 (LOD=2.83) and eight minor candidate regions 2q12-q33, 3q13, 4p15-q12, 5q13-q15, 6p24-p23, 12p13, 22q13, and Xp21 (LOD=1.04-1.63) likely to contain susceptibility genes for allergic rhinitis. Our findings did not support a previous report of linkage of allergic rhinitis to chromosome 12q14-q24 but they added positive evidence to the asthma and atopy candidate regions 2q33 and 6p23. Further identification of the specific genes involved in allergic rhinitis will give opportunities for improved diagnosis and treatment.

A new locus for Seckel syndrome on chromosome 18p11.31-q11.2.

Seckel syndrome (MIM 210600) is a rare autosomal recessive disorder with a heterogeneous appearance. Key features are growth retardation, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance. We have performed a genome-wide linkage scan in a consanguineous family of Iraqi descent. By homozygosity mapping a new locus for the syndrome was assigned to a approximately 30 cM interval between markers D18S78 and D18S866 with a maximum multipoint lod score of 3.1, corresponding to a trans-centromeric region on chromosome 18p11.31-q11.2. This second locus for Seckel syndrome demonstrates genetic heterogeneity and brings us a step further towards molecular genetic delineation of this heterogeneous condition.

Association analyses suggest GPR24 as a shared susceptibility gene for bipolar affective disorder and schizophrenia.

Linkage analyses suggest that chromosome 22q12-13 may harbor a shared susceptibility locus for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of a sample from the Faeroe Islands we have previously reported association between both disorders and microsatellite markers in a 3.6 cM segment on 22q13. The present study investigated three candidate genes located in this segment: GPR24, ADSL, and ST13. Nine SNPs located in these genes and one microsatellite marker (D22S279) were applied in an association analysis of two samples: an extension of the previously analyzed Faeroese sample comprising 28 distantly related cases (17 BPD, 11 SZ subjects) and 44 controls, and a Scottish sample including 162 patients with BPD, 103 with SZ, and 200 controls. In both samples significant associations were observed in both disorders with predominantly GPR24 SNPs and haplotypes. In the Faeroese sample overall P-values of 0.0009, 0.0054, and 0.0023 were found for haplotypes in BPD, SZ, and combined cases, respectively, and in the Scottish sample overall P-values of 0.0003, 0.0005, and 0.016 were observed for similar groupings. Specific haplotypes showed associations with lowest P-values of 7 x 10(-5) and 0.0006 in the combined group of cases from the Faeroe Islands and Scotland, respectively. The G protein-coupled receptor 24 encoded by GPR24 binds melanin-concentrating hormone (MCH) and has been implicated with feeding behavior, energy metabolism, and regulation of stress and mood. To our knowledge this is the first study reporting association between GPR24 and BPD and SZ, suggesting that GPR24 variants may confer susceptibility to both disorders.

Fine-scale mapping of type I allergy candidate loci suggests central susceptibility genes on chromosomes 3q, 4q and Xp.

BACKGROUND: Type I allergy globally affects an increasing number of individuals with the consequence of considerable personal morbidity and socio-economic costs. Identification of disease susceptibility genes would render enormous medical perspectives in terms of improved diagnosis, treatment and prevention. Like for other complex disorders, achievement of the knowledge necessary depends on confirmation of reported genomic candidate regions. METHODS: We performed a two-stage fine-scale linkage analysis in 11 selected candidate regions on chromosome 3p, 3q, 4p, 4q, 5q, 6p, 9p, 12q, 12qter, 18q and Xp. We analysed 97 polymorphic markers in 424 individuals from 100 sib-pair families and evaluated the data for five phenotypes: Allergic asthma, atopic dermatitis, allergic rhinitis and total and specific immunoglobulin E. RESULTS: The highest maximum likelihood scores (MLS) were obtained on chromosomes 3q (MLS = 2.69), 4p (MLS = 2.34), 4q (MLS = 2.75), 6p (MLS = 2.22), 12qter (MLS = 2.15) and Xp (MLS = 2.23). All five phenotypes showed MLS >/= 2 in one or more of the candidate regions. CONCLUSIONS: Susceptibility genes in the 3q, 4q and Xp regions may play a central role in the inheritance of allergic disease, as positive results were obtained for all five phenotypes in these three regions.

No linkage and association of atopy to chromosome 16 including the interleukin-4 receptor gene.

BACKGROUND: Several susceptibility genes for atopy have been suggested in recent years. Few have been investigated as intensively as the interleukin-4-receptor alpha (IL4Ralpha) gene on chromosome 16. The results remain in dispute. Therefore, in a robust design, we tested for association of type I allergy to the IL4R variations I50V and Q576R, and investigated chromosome 16 for atopy candidate regions in general. METHODS: We identified 100 Danish allergy sib-pair families. Five conservative phenotypes for type I allergy were defined and evaluated. The IL4R variations were genotyped in trios and evaluated by the transmission disequilibrium test (TDT). Multipoint linkage analysis and exclusion mapping were conducted with sib-pairs analyzed for 17 microsatellite markers. RESULTS: No evidence for association or linkage to the IL4R polymorphisms was found (P values: 0.12-0.90). Linkage analysis did not support linkage of any of the phenotypes to chromosome 16. Major parts of chromosome 16 were excluded as candidate regions harboring oligogenes for type I allergy. CONCLUSION: We found chromosome 16 unlikely to harbor strong candidate genes for type I allergy. The role of the IL4Ralpha gene in the inheritance of atopy was insignificant in the Danish population. The use of conservative allergy phenotypes in the search for genes predisposing to atopic disease was discussed.

Asthma and atopy - a total genome scan for susceptibility genes.

BACKGROUND: Allergic asthma is an increasingly common disease of complex inheritance. Several studies have suggested candidate regions, but genetic heterogeneity, ethnic differences and varying study designs may in part explain the lack of identified and confirmed susceptibility genes. Investigation of different populations will further clarify the topic. We therefore evaluated allergic asthma and increased total and specific IgE in 39, 45 and 57 sib-pairs from 100 Danish allergy families. METHODS: Affected sib-pairs meeting a narrow phenotype definition were selected for the three phenotypes atopy, allergic asthma and increased total IgE. We performed a total genome scan using 446 microsatellite markers and obtained nonparametric linkage results from the MAPMAKER/SIBS computer program. RESULTS: Our study revealed four candidate regions (MLS > 2) on chromosome 1p36, 3q21-q22, 5q31 and 6p24-p22, and 15 candidate regions (1 < MLS < 2) that may contain susceptibility genes for asthma and atopy. We did not find linkage to the candidate genes TNF-beta, FcER1beta and Il4R-alpha, except for weak support for linkage of the asthma phenotype to TNF-beta (MLS = 1.18). CONCLUSIONS: We found evidence for two new asthma and atopy loci, 1p36 and 3q21-q22, and supported linkage in the Danish population to seven previously reported candidate regions.