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A letter to the editor is presented which discusses a study regarding Hidradenitis suppurativa (HS), a chronic inflammatory dermatosis, and the effect of haploinsufficiency of gamma-secretase components in gamma-secretase enzyme activity in vitro.

Explains that medical genetics researchers have conducted detailed dosimetric analysis in 20 patients with monosomy 2q37. Minimum deleted region in patients with characteristic facial dysmorphism and Albright hereditary osteodystrophy-like brachymetaphalangism; No clear genotype-phenotype correlations could be drawn that would help predict clinical prognosis.

Background: Mutations of the transforming growth factor β (TGFβ) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. Objective: To investigate kindreds presenting with both pulmonary hypertension and HHT. Methods: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular Iocalisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. Results: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. Conclusions: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease. [ABSTRACT FROM AUTHOR]

Investigates the validity of the hypothesis of corneodesmosin (CDSN) involvement in psoriasis. Confirmation that the rare haplotype cluster D is a risk haplotype originating from the Gujurat region of northern India; Definition of CDSN genetic variation by an association study of intragenic single nucleotide polymorphism (SNP) haplotypes; Identification of 16 SNP chromosomes conferring significant disease risk both in the UK and the Gujuriti data sets.

Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed a genome wide linkage search using autozygosity mapping in a cohort of four consanguineous families with ATD, three of which originate from Pakistan, and one from southern Italy. In these families, as well as in a fifth consanguineous family from France, we localised a novel ATD locus (ATD) to chromosome 15q13, with a maximum cumulative two point lod score at D15S1031 (Zmax = 3.77 at θ=0.00). Five consanguineous families shared a 1.2 cM region of homozygosity between D15S165 and D15S1010. Investigation of a further four European kindreds, with no known parental consanguinity, showed evidence of marker homozygosity across a similar interval. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of two candidate genes, GREMLIN and FORMIN, did not show pathogenic mutations. [ABSTRACT FROM AUTHOR]

Examines the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis. Family pedigree; Mutation analysis of candidate gene; Phototransduction pathway.

Chronic plaque psoriasis affects approximately 1.6%, of the P.K. population. Population, family and twin studies all strongly suggest an important genetic component in the pathogenesis of the disease. although genetic linkage studies have, so far, failed to identify susceptibility genes. We describe a family in which psoriasis cosegregates through three generations with a known autosomal dominant disorder, hereditary multiple exostoses IHME). A major locus for HME has recently been mapped to chromosome 8q. Observations in this family may provide a mapping clue for a psoriasis susceptibility gene. [ABSTRACT FROM AUTHOR]

Explains that genetic analysis of susceptibility locus PSORS2 markers in a Great Britain dataset supports the association between RAPTOR single nucleotide polymorphisms SNPs and familial psoriasis. Multifactorial skin disorder; PSOSRS maps to the Major Histocompatibility Complex on chromosome 6p21; Two distinct association peaks.

Examines the prevalence of an allelic variant of the apoprotein AI-CIII-AIV gene cluster in non-insulin-dependent diabetes. Role of a genetic component in the etiology of the disease; Predisposition of DNA variation to atherosclerosis; Incidence of coronary heart disease in non-insulin-dependent diabetes.

Abstract: Pelizaeus–Merzbacher-like disease (PMLD) is a clinically and genetically heterogeneous neurological disorder of cerebral hypomyelination. It is clinically characterised by early onset (usually infantile) nystagmus, impaired motor development, ataxia, choreoathetoid movements, dysarthria and progressive limb spasticity. We undertook autozygosity mapping studies in a large consanguineous family of Pakistani origin in which affected children had progressive lower limb spasticity and features of cerebral hypomyelination on MR brain imaging. SNP microarray and microsatellite marker analysis demonstrated linkage to chromosome 1q42.13–1q42.2. Direct sequencing of the gap junction protein gamma-2 gene, GJC2, identified a promoter region mutation (c.-167A>G) in the non-coding exon 1. The c.-167A>G promoter mutation was identified in a further 4 individuals from two families (who were also of Pakistani origin) with clinical and radiological features of PMLD in whom previous routine diagnostic screening of GJC2 had been reported as negative. A common haplotype was identified at the GJC2 locus in the three mutation-positive families, consistent with a common origin for the mutation and likely founder effect. This promoter mutation has only recently been reported in GJC2-PMLD but it has been postulated to affect the binding of the transcription factor SOX10 and appears to be a prevalent mutation, accounting for ~29% of reported patients with GJC2-PMLD. We propose that diagnostic screening of GJC2 should include sequence analysis of the non-coding exon 1, as well as the coding regions to avoid misdiagnosis or diagnostic delay in suspected PMLD. [Copyright &y& Elsevier]