In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome.

Using high-resolution molecular karyotyping with SNP arrays to identify candidate genes for etiologically unexplained intellectual disability, we identified a 32-kb de novo in-frame deletion of the C-terminal helicase domain of the SMARCA2 gene in a patient with severe intellectual disability, epilepsy, sparse hair, prominent joints, and distinct facial anomalies. Sequencing of the gene in patients with a similar phenotype revealed de novo missense mutations in this domain in 2 further patients, pointing to a crucial role of the SMARCA2 C-terminal helicase domain. The clinical features observed in all 3 patients are typical of Nicolaides-Baraitser syndrome, an only rarely reported syndrome with mainly moderate to severe intellectual disability. Notably, one of our patients with a p.Gly1132Asp mutation showed typical morphological features but an exceptional good development with borderline overall IQ and learning difficulties, thus expanding the phenotypic spectrum of Nicolaides-Baraitser syndrome.

Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1.

BACKGROUND: Psoriasis is a genetically complex, chronic inflammatory skin disease. The authors have previously identified a susceptibility locus on chromosome 19p13 (PSORS6). METHODS AND RESULTS: In a follow-up linkage disequilibrium (LD) study in an independent family based cohort, the authors found evidence for association to a newly discovered microsatellite at this locus (D19SPS21, p<5.3x10(-5)). An LD based association scan in 300 trios revealed association to several single, single nucleotide polymorphisms (SNPs) in one LD block. When the authors stratified this cohort for carrying the PSORS1 risk allele at the HLA-C locus, evidence for association became much stronger at single SNP and haplotype levels (p values between 1.0x10(-4) and 8.0x10(-4)). In a replication study of 1114 patients and 937 control individuals, evidence for association was also observed after stratification to the PSORS1 risk allele. In both study groups, logistic regression showed evidence for interaction between the risk alleles at PSORS1 and PSORS6. Best p values for rs12459358 in both study groups remained significant after correction for multiple testing. The associated LD block did not comprise any known genes. Interestingly, an adjacent gene, MUC16, coding for a large glycosylated protein expressed in epithelia and of unknown function, could be shown to be also expressed in tissues relevant for pathogenesis of psoriasis such as skin and thymus. Immunohistochemical analyses of skin revealed focal staining for MUC16 in suprabasal epidermal cells. Further functional studies are required to clarify its potential role in psoriasis and identify the causal variant(s) at this locus. CONCLUSION: The data establish PSORS6 as a confirmed psoriasis susceptibility locus showing interaction with PSORS1.

Polymorphisms of human estrogen receptor (ER) gene alpha and beta in prostate cancer PC-EW and PC-OR cell lines.

BACKGROUND: Prostate cancer is the second leading cause of death among men in Western countries. Genetic alterations of the estrogen receptor gene are known to be indicative of a higher risk of this disease. The estrogen receptor gene is found as two subtypes, alpha and beta. In this study the estrogen receptor alpha and beta genes were tested in 2 human prostate cancer cell lines: the hormone-sensitive PC-EW and the hormone-independent PC-OR. MATERIALS AND METHODS: Genomic DNA was isolated from 2 cell lines from metastatic prostate adenocarcinoma in hetero-transplanted male athymic nude (nu/nu) Balb/c mice. Mutation screening was performed by sequencing of exons 1-8 and intron 1 of the human estrogen receptor gene alpha, and exons 1-9 of estrogen receptor gene beta. RESULTS: No point mutations were detected in the ER gene subtypes of either cell line. Polymorphisms were found of ER-alpha in exon 1, intron 1, exon 3, 4, 5, intron 6 and exon 8 and of ER-beta in intron 2 and exon 9. CONCLUSION: Point mutations of ER-alpha and -beta are not necessary for metastatic prostate cancer, alterations in different areas of the ER genes are more often found. These polymorphisms are a part of many genetic influences that accumulate to contribute to men's overall risk for developing prostate cancer.

LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients.

Deletions within human chromosome 4p16.3 cause Wolf-Hirschhorn syndrome (WHS), which is characterized by severe mental and developmental defects. It is thought that haploinsufficiency of more than one gene contributes to the complex phenotype. We have cloned and characterized a novel gene (LETM1) that is deleted in nearly all WHS patients. LETM1 encodes a putative member of the EF-hand family of Ca(2+)-binding proteins. The protein contains two EF-hands, a transmembrane domain, a leucine zipper, and several coiled-coil domains. On the basis of its possible Ca(2+)-binding property and involvement in Ca(2+) signaling and/or homeostasis, we propose that haploinsufficiency of LETM1 may contribute to the neuromuscular features of WHS patients.

Identification of novel exons 3' to the human SNRPN gene.

The gene for the small nuclear ribonucleoprotein N (SNRPN) maps to human chromosome 15 and has 10 exons. Using cDNA cloning, direct cDNA selection, and exon-connection reverse transcriptase (RT)-PCR, we have identified three novel 3' exons of SNRPN, which have no protein coding potential. Like the other SNRPN exons, the novel exons are expressed from the paternal allele only. In contrast to several cDNA clones and RT-PCR products, however, the 3.4-kb transcript detected by Northern blot hybridization with a probe for the novel exons does not contain SNRPN. It is possible that the steady-state RNA observed in fetal tissues and in adult testis, ovary, brain, and muscle is initiated at an as yet unidentified transcription start site downstream of SNRPN or is generated by endonucleolytic cleavage of a precursor transcript, as has been shown for another imprinted gene, the insulin-like growth factor II gene.

Human CLAPS2 encoding AP17, a small chain of the clathrin-associated protein complex: cDNA cloning and chromosomal assignment to 19q13.2-->q13.3.

We have cloned the cDNA for the human homolog of the rat AP17 gene, a small chain of the clathrin-associated protein complex AP-2. The cDNA is highly conserved between rat and human. Human AP17, gene symbol CLAPS2 (clathrin-associated/assembly/adaptor protein, small 3, 17 kDa), was assigned to chromosome region 19q13.2-->q13.3.