Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function

Erik G. Puffenberger, Diane Hu-Lince, Jennifer M. Parod, David W. Craig, Seth E. Dobrin, Andrew R. Conway, Elizabeth A. Donarum, Kevin A. Strauss, Travis Dunckley, Javier F. Cardenas, Kara R. Melmed, Courtney A. Wright, Winnie Liang, Phillip Stafford, C. Robert Flynn, D. Holmes Morton, Dietrich A. Stephan

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Abstract

We have identified a lethal phenotype characterized by sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males [Online Mendelian Inheritance in Man (OMIM) accession no. 608800]. Twenty-one affected individuals with this autosomal recessive syndrome were ascertained in nine separate sibships among the Old Order Amish. High-density single-nucleotide polymorphism (SNP) genotyping arrays containing 11,555 single-nucleotide polymorphisms evenly distributed across the human genome were used to map the disease locus. A genome-wide autozygosity scan localized the disease gene to a 3.6-Mb interval on chromosome 6q22.1-q22.31. This interval contained 27 genes, including two testis-specific Y-like genes (TSPYL and TSPYL4) of unknown function. Sequence analysis of the TSPYL gene in affected individuals identified a homozygous frameshift mutation (457_458insG) at codon 153, resulting in truncation of translation at codon 169. Truncation leads to loss of a peptide domain with strong homology to the nucleosome assembly protein family. GFP-fusion expression constructs were constructed and illustrated loss of nuclear localization of truncated TSPYL, suggesting loss of a nuclear localization patch in addition to loss of the nucleosome assembly domain. These results shed light on the pathogenesis of a disorder of sexual differentiation and brainstem-mediated sudden death, as well as give insight into a mechanism of transcriptional regulation.

Original languageEnglish (US)
Pages (from-to)11689-11694
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number32
DOIs
StatePublished - Aug 10 2004

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    Puffenberger, E. G., Hu-Lince, D., Parod, J. M., Craig, D. W., Dobrin, S. E., Conway, A. R., Donarum, E. A., Strauss, K. A., Dunckley, T., Cardenas, J. F., Melmed, K. R., Wright, C. A., Liang, W., Stafford, P., Flynn, C. R., Morton, D. H., & Stephan, D. A. (2004). Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function. Proceedings of the National Academy of Sciences of the United States of America, 101(32), 11689-11694. https://doi.org/10.1073/pnas.0401194101