To the Editor: Psoriasis vulgaris is a chronic inflammatory skin disease which affects approximately 2–5% of the Caucasian population (1). The etiology of this disorder is largely unknown (2). Familial clustering (3) and a high concordance rate in monozygotic compared to dizygotic twins (4) indicates a strong contribution of genetic susceptibility factors. Genome-wide linkage analyzes have identified 19 susceptibility loci to date (5). The PSORS1 locus on 6p21.3 has been consistently reproduced in several independent studies (6–11). Linkage to 4q31 (PSORS9) was found in a large cohort of Chinese Han families (10). A meta-analysis combining the results of six genome-wide scans and a recent study in the Icelandic population confirmed significant linkage to PSORS9 on 4q31 (5, 11). However, as is the case for other complex disorders, positional cloning of psoriasis disease genes faces substantial difficulties due to genetic heterogeneity, the multitude of genetic risk factors, and the fact that there are different risk factors in different populations. No psoriasis susceptibility gene in 4q31 has been identified to date. Breakpoint analyzes in patients with balanced chromosome rearrangements have led to the identification of numerous genes involved in monogenic disorders (12) and facilitated the detection of candidate genes for complex and late-onset diseases, e.g., schizophrenia (13) and developmental dyslexia (14). Here, we describe a 43-year-old male patient with a balanced translocation 46,XY,t(2;4) (p25;q31.1) (Fig. 1a) and familial psoriasis vulgaris. The proband has suffered from psoriasis vulgaris since the age of 20. The father of our proband, who died of a heart attack at the age of 62, also suffered from psoriasis, and, unlike his son, he had additional arthritic problems. No chromosome analysis was performed; however, we speculate that he was also a carrier of this translocation because two female partners had multiple spontaneous abortions. No other relatives were available for chromosome analysis, and no other family members were known to have suffered from psoriasis. (a) Ideograms depicting normal chromosomes 2 (red) and 4 (green) and their derivatives der(2) and der(4), and breakpoints (arrows). (b) Patient metaphase chromosomes used for FISH with the breakpoint-spanning BAC RP11-1079H4 (red signal). (c) Southern blot. C, control; P, patient; and aberrant bands are marked with arrows. (d) Partial sequence chromatogram of the fusion product, showing the flanking sequence of chromosome 4 and the sequence of chromosome 2. (e) Results of RT-PCR for CR742434. Molecular cytogenetic breakpoint analysis by FISH experiments (15) using YAC and BAC clones listed in Table 1 revealed breakpoint-spanning BAC clones on chromosome 2 (RP11-796O1, which contains no genes) and on chromosome 4 [RP11-1079H4 (Fig. 1b) and RP11-90M18]. The presence of several genes in this region –SET7, MGST2 and MAML3– prompted us to determine the breakpoint at the molecular level. For Southern blot analysis, patient and control genomic DNA samples were digested with several restriction enzymes and hybridized with α32[P]dCTP-labeled DNA probes derived from BAC RP11-1079H4. Hybridization with probe PSORPZ (amplified with the following primers: 5′-AGAGTGAGGCCTTCTCAGCA-3′ and 5′-GCCATGTTTCCAGGTTACCA-3′) revealed aberrant fragments exclusively in patient DNA digested with restriction enzymes SspI, MboI, and PstI (Fig. 1c). Polymerase chain reaction (PCR) on adaptor-ligated genomic DNA was performed as described previously (16) for breakpoint cloning. Patient genomic DNA was digested with MboI. Amplification was performed using adaptor-specific primers and chromosome 4-specific nested primers. Sequencing of the cloned PCR product revealed a fusion fragment that aligned to chromosomes 4 and 2 (Fig. 1d), which indicated the breakpoint location between position chr4:140,938,199 and chr4:140,938,200 on the UCSC Genome Browser May 2004 assembly. The breakpoint lies within intron 3 of EST CR742434, 6581 bp upstream of the start codon of MGST2 (Fig. 2). Schematic representation of known genes within 500 kb 5′ and 3′ of the breakpoint on chromosome 4, the exon–intron structures of MGST2 and EST CR742434 on the complementary DNA strands (not to scale), and the breakpoint in our patient (vertical bar). Note the overlap of 127 bp of MGST2 exon 1 and CR742434 exon 2. Both semiquantitative RT-PCR and Northern blot investigations of MGST2 failed to detect quantitative differences between patient and control mRNA from lymphoblastoid cells. We have detected expression of EST CR742434 by RT-PCR in lymphoblastoid cells and fibroblasts. RT-PCRs using a forward primer in exon 2 (5′-GTAGAGCGCACGGGAAGATA-3′) and a reverse primer in exon 4 (5′-TTCACTAATCCCTGGCGTTC-3′) resulted in fragments of the expected size (274 bp) and a smaller fragment of 166 bp that lacks exon 3 (Fig. 1e). EST CR742434 is a spliced non-coding antisense RNA gene partially overlapping MGST2 on the opposite DNA strand (Fig. 2). It is tempting to speculate that the truncation of the last two exons of CR742434 in our patient alters its properties, e.g. by changing its stability or its cellular localization, which in turn may lead to altered expression of the MGST2 gene. Regulation of gene expression by antisense RNA is known to occur in both prokaryotic and eukaryotic organisms (17). Antisense transcripts can affect post-transcriptional events such as splicing, RNA transport, cytoplasmic stability, and translation (18–23). In light of this, it is plausible that the disruption of CR742434 could result in dysregulation of MGST2, although we have failed to detect expression changes in lymphoblastoid cells of our patient. Subtle gene expression or tissue-specific expression effects could have escaped our semiquantitative RT-PCR analysis. Leukotrienes are important mediators of inflammation. Microsomal glutathione S-transferase 2 (MGST2) is a major enzyme catalyzing the conjugation of leukotriene A4 (LTA4) to glutathione, which produces leukotriene C4 (LTC4) (24). Altered expression of MGST2 could affect the conversion of LTA4 into LTC4 in some tissues. Accumulating LTA4 might in turn be metabolized in the alternative leukotriene A4 hydrolase pathway into (excess) LTB4, which is found in elevated levels in psoriatic lesions (25). The role of MGST2 in leukotriene metabolism and its location within the PSORS9 genomic region make it a functional and positional candidate gene for inflammatory diseases like psoriasis. However, with a common phenotype such as psoriasis and no firm familial segregation data for the balanced translocation, we cannot rule out the possibility that this is a chance finding. Additionally, position effects on the expression of genes as distant as 1 Mb from the chromosome breakpoint might constitute alternative disease-causing mechanisms (26, 27). The known genes within 500 kb on the 5′ side (SET7, RAB33B, NARG1, NDUC1 and OSAP) and the 3′ side (MAML3) are depicted in Fig. 2. No specific involvement in inflammatory processes and/or structural components of skin tissue cells is known for any of these genes; therefore, we consider them to be less promising than MGST2/CR742434 as candidate genes for psoriasis vulgaris. Mutation screening or association studies in large cohorts of psoriasis patients, preferably in familial cases with linkage to 4q31.1, are required in order to confirm a role for MGST2 and/or CR742434 variants in psoriasis. Such studies might have far reaching consequences for the diagnosis and treatment of this disorder. We thank Petra Viertel, Hannelore Madle and Susanne Freier for technical assistance, and Sarah Shoichet for careful reading of the manuscript. We gratefully acknowledge support from the German National Genome Research Network (NGFN, project number 01GR0105).

Nonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of these genes cluster on the proximal Xp, which prompted us to perform systematic mutation screening in brain-expressed genes from this region. Here, we report on a novel NSXLMR gene, FTSJ1, which harbors mutations in three unrelated families--one with a splicing defect, one with a nonsense mutation, and one with a deletion of one nucleotide. In two families, subsequent expression studies showed complete absence or significant reduction of mutant FTSJ1 transcripts. FTSJ1 protein is a homolog of Escherichia coli RNA methyltransferase FtsJ/RrmJ and may play a role in the regulation of translation. Further studies aim to elucidate the function of human FTSJ1 and its role during brain development.

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.

Nonsyndromic X-linked mental retardation (MRX) is defined by an X-linked inheritance pattern of low IQ, problems with adaptive behavior, and the absence of additional specific clinical features. The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families. In a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21), we have cloned the DNA fragment that contains the X-chromosomal and the autosomal breakpoint. In silico sequence analysis provided no indication of a causative role for the chromosome 7 breakpoint in mental retardation (MR), whereas, on the X chromosome, a zinc-finger gene, ZNF41, was found to be disrupted. Expression studies indicated that ZNF41 transcripts are absent in the patient cell line, suggesting that the mental disorder in this patient results from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals. A proline-to-leucine amino acid exchange is present in affected members of one family with MRX. A second family carries an intronic splice-site mutation that results in loss of specific ZNF41 splice variants. Wild-type ZNF41 contains a highly conserved transcriptional repressor domain that is linked to mechanisms of chromatin remodeling, a process that is defective in various other forms of MR. Our results suggest that ZNF41 is critical for cognitive development; further studies aim to elucidate the specific mechanisms by which ZNF41 alterations lead to MR.