Investigation of gamma secretase gene complex mutations in German population with Hidradenitis suppurativa designate a complex polygenic heritage.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease affecting apocrine gland-bearing skin in the axilla, groin and under the breasts. Mutations of the gamma secretase gene complex, which is essential in the activation of Notch signalling pathways, were shown in some families with HS and in a few sporadic cases. Although an imbalance in Notch signalling is implicated in the pathogenesis, the exact mechanism of HS development is yet unknown. OBJECTIVES: We aim to investigate the genetic basis of HS by determining the presence of mutations of gamma secretase gene complex in a cohort of HS patients and by searching for a disease-causing pathogenic variant in a multi-generational HS family using parametric linkage analysis. METHODS: Thirty-eight patients clinically diagnosed with HS were included in this study. All exons and exon-intron boundaries of the genes encoding gamma secretase complex consisting of six genes: APH1A, APH1B, PSENEN, NCSTN, PSEN1 and PSEN2 were sequenced by Sanger technique. Genetic mapping with parametric linkage analysis for the patients in the family was performed with eight affected and four healthy individuals. The logarithm of odds was calculated. RESULTS: In a sporadic patient with early-onset, severe lesions in axilla and groin, a novel single-nucleotide deletion causing frameshift in exon 1 of the NCSTN gene was identified ((NM_015331.3): c.38delG, p.(Gly13Glufs*15)). The LOD score of 1.5 was never exceeded in any region of the genome, pointing towards intricate multi-genic inheritance pattern within the affected family. CONCLUSIONS: The gamma secretase gene complex mutations were rare in our cohort (3.2%). Besides, our analysis indicates a possible complex multi-genic inheritance in a seemingly autosomal dominantly inherited large HS family. Genetics of both familial and sporadic HS may be complicated in most cases, and the role of other potential genes such as autoinflammatory and modifier genes as well as environmental factors may influence the pathogenesis.

Homozygous XYLT2 variants as a cause of spondyloocular syndrome.

Spondyloocular syndrome (SOS) is a rare autosomal recessive, skeletal disorder. Two recent studies have shown that it is the result of biallelic sequence variants in the XYLT2 gene with pleiotropic effects in multiple organs, including retina, heart muscle, inner ear, cartilage, and bone. The XYLT2 gene encodes xylosyltransferase 2, which catalyzes the transfer of xylose (monosaccharide) to the core protein of proteoglycans (PGs) leading to initiating the process of PG assembly. SOS was originally characterized in 2 families A and B of Iraqi and Turkish origin, respectively. Using DNA from affected members of the same 2 families, we performed whole exome sequencing, which revealed 2 novel homozygous missense variants (c.1159C > T, p.Arg387Trp) and (c.2548G > C, p.Asp850His). Our findings extend the body of evidence that SOS is caused by homozygous variants in the XYLT2 gene. In addition, this report has extended the phenotypic description of SOS by adding follow-up data from 5 affected individuals in one of the two families, presented here.

Pili annulati: refinement of the locus on chromosome 12q24.33 to a 2.9-Mb interval and candidate gene analysis.

BACKGROUND: Pili annulati is an autosomal dominant hair shaft disorder characterized by alternating light and dark bands in hairs of affected individuals. Recently, a locus for pili annulati was mapped to chromosome 12q24.32-24.33 and recombination events defined a critical region of 9.2 cM (3.9 Mb). OBJECTIVES: The aim of the current study was to narrow the size of the candidate region and to identify the pathogenic mutation for pili annulati by analysing the candidate genes. METHODS: In three families with 90 individuals, including 40 affected subjects, linkage analysis was performed with 13 microsatellite markers in the candidate region on chromosome 12. Candidate genes were analysed for their expression in hair follicles and other tissues by reverse transcriptase-polymerase chain reaction (RT-PCR) and mutation analysis. RESULTS: Multipoint LOD score analysis for all three families confirmed the locus on the long arm of chromosome 12 with a maximum LOD score of 12.26 at marker D12S357. In two families, recombinations were identified which narrowed the region to 2.9 Mb containing 36 genes. We analysed the candidate genes in this region by RT-PCR and found that 24 were expressed in human hair follicles. Based on the result of the expression analysis, DNA sequencing of the coding region of the candidate genes was performed; this did not result in the discovery of a causal mutation. CONCLUSION: We reduced the critical interval of pili annulati to 2.9 Mb and excluded mutations in the coding region of all 36 possible candidate genes by sequence analysis.

Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia.

Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14-11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3' untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P=0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.

[A patient flow analysis within the Munich addiction treatment system--a pilot study]. / Patientenstromanalyse im Münchner Suchthilfesystem - eine Pilotstudie.

BACKGROUND: The highest efficiency in addiction treatment is attributed to a multistage programme consisting of several intervention types (e. g., counselling, withdrawal, therapy, community adjustment) in a specific order. AIM: The pilot study described focuses on the interactions between treatment modalities (i. e. on the process quality) within the addiction treatment system in Munich and the broader environs. METHOD: In eleven institutions out of the several intervention types 452 persons were anonymously queried. The interview was conducted by means of a questionnaire, which gathered information about the sequence of interventions. RESULTS: The results suggest that the treatment sequences (i. e. the patient flow) investigated are consistent with the intended cooperation within the multistage treatment programme. Furthermore, the results also indicate that more than a quarter of the participants came sought treatment/counselling of their own initiative. Particularly interesting is the observation that the participating institutions rarely checked where "their" patients pursue aftercare/treatment follow-up upon completion of the prescribed programme. Regarding the actual referrals during the four week investigation period, relatively low referrals among the participants in the drop-in center were observed. CRITICISM: It remains doubtful whether the selected institutions are really representative of the different intervention types, because the participating institutions within an intervention type operate from diverse conceptual backgrounds. Furthermore, the sample size obtained was both small and contained a diverse number of participants per institution type. Therefore, whether or not the results can be generalized is questionable. CONCLUSION: Based on these results the BAS supports the deployment and legal establishment of case managers in the coordination of a patient's global treatment process. It is believed that this step would result in a more purposeful and economical treatment within the multistage addiction treatment programme.

First results on label-free detection of DNA and protein molecules using a novel integrated sensor technology based on gravimetric detection principles.

A novel integrated bio-sensor technology based on thin-film bulk acoustic wave resonators on silicon is presented and the feasibility of detecting DNA and protein molecules proofed. The detection principle of these sensors is label-free and relies on a resonance frequency shift caused by mass loading of an acoustic resonator, a principle very well known from quartz crystal micro balances. Integrated ZnO bulk acoustic wave resonators with resonance frequencies around 2 GHz have been fabricated, employing an acoustic mirror for isolation from the silicon substrate. DNA oligos have been thiol-coupled to the gold electrode by on-wafer dispensing. In a further step, samples have either been hybridised or alternatively a protein has been coupled to the receptor. The measurement results show the new bio-sensor being capable of both, detecting proteins as well as the DNA hybridisation without using a label. Due to the substantially higher oscillation frequency, these sensors already show much higher sensitivity and resolution comparable to quartz crystal micro balances. The potential for these sensors and sensors arrays as well as technological challenges will be discussed in detail.

A genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6.

Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.

Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis.

Suggestive evidence for a potential susceptibility locus for schizophrenia at 5q31 was obtained in two family samples. Sample I consisted of 14 families with schizophrenia and revealed for the marker IL9 a lod score of 1.8 by two point lod score analysis. Sample II comprised 44 families including four from sample I and was ascertained in order to employ affected sib-pair analysis by identity by descent. A lod score of 1.8 around the marker D5S399 was obtained by multipoint analysis. The lod score remained positive, but decreased to 1.27 when the four families from sample I were excluded in order to use sample II as a statistically independent replication sample. We propose a susceptibility locus for schizophrenia with probably minor contribution in the pedigrees under investigation.

[Is mere surgical division of the transverse carpal ligament in treatment of carpal tunnel syndrome adequate?]. / Ist die blosse chirurgische Spaltung des Ligamentum carpi transversum zur Behandlung des Carpaltunnel-Syndroms ausreichend?

In the period between 1985-1986 137 patients underwent simple nerve decompression by division of the carpal ligament as therapy for carpal tunnel syndrome. In a long-term follow-up it was possible to control the results of 61 cases. Beside two patients all showed an absolutely satisfying result, subjectively as well as electroneurophysiologically. Therefore we can recommend simple ligament division as a safe and quick method for the therapy of carpal tunnel syndrome.