Abstract
BackgroundMutations in genes whose products modify chromatin structure have been recognized as a cause of X-linked mental retardation (XLMR). These genes encode proteins that regulate DNA methylation (MeCP2), modify histones (RSK2 and JARID1C), and remodel nucleosomes through ATP hydrolysis (ATRX). Thus, genes encoding other chromatin modifying proteins should also be considered as disease candidate genes. In this work, we have characterized the SNF2L gene, encoding an ATP-dependent chromatin remodeling protein of the ISWI family, and sequenced the gene in patients from 12 XLMR families linked to Xq25-26.MethodsWe used an in silico and RT-PCR approach to fully characterize specific SNF2L isoforms. Mutation screening was performed in 12 patients from individual families with syndromic or non-syndromic XLMR. We sequenced each of the 25 exons encompassing the entire coding region, complete 5' and 3' untranslated regions, and consensus splice-sites.ResultsThe SNF2L gene spans 77 kb and is encoded by 25 exons that undergo alternate splicing to generate several distinct transcripts. Specific isoforms are generated through the alternate use of exons 1 and 13, and by the use of alternate donor splice sites within exon 24. Alternate splicing within exon 24 removes a NLS sequence and alters the subcellular distribution of the SNF2L protein. We identified 3 single nucleotide polymorphisms but no mutations in our 12 patients.ConclusionOur results demonstrate that there are numerous splice variants of SNF2L that are expressed in multiple cell types and which alter subcellular localization and function. SNF2L mutations are not a cause of XLMR in our cohort of patients, although we cannot exclude the possibility that regulatory mutations might exist. Nonetheless, SNF2L remains a candidate for XLMR localized to Xq25-26, including the Shashi XLMR syndrome.
Highlights
Mutations in genes whose products modify chromatin structure have been recognized as a cause of X-linked mental retardation (XLMR)
The isolation of genes underlying X-linked mental retardation (XLMR) disorders has been hampered, in part, by the broad phenotypic variability observed in patients that restricts linkage analysis to large single families or instances where a specific trait facilitates phenotypic splitting
The cloning of the ATRX gene as the cause of the α-thalassemia mental retardation (ATR-X) syndrome established the paradigm for chromatin remodeling proteins in neurodevelopmental disorders [2]
Summary
Mutations in genes whose products modify chromatin structure have been recognized as a cause of X-linked mental retardation (XLMR) These genes encode proteins that regulate DNA methylation (MeCP2), modify histones (RSK2 and JARID1C), and remodel nucleosomes through ATP hydrolysis (ATRX). The PHF6 (Borjeson-Forssman-Lehmann syndrome;[10]), ZNF41 [11], ZNF81 [12], and JARID1C [13] genes have been implicated in XLMR and have roles in transcriptional regulation and/or chromatin remodeling Taken together, these studies suggest that additional chromatin interacting proteins whose genes reside on the X chromosome should be considered as disease candidates for both syndromal and non-specific XLMR disorders
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