Mapping of Sudden Infant Death with Dysgenesis of the Testes Syndrome (SIDDT) by a SNP Genome Scan and Identification of TSPYL Loss of Function

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 ascer...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2004-08, Vol.101 (32), p.11689-11694
Main Authors: Puffenberger, Erik G., Hu-Lince, Diane, Parod, Jennifer M., Craig, David W., Dobrin, Seth E., Conway, Andrew R., Donarum, Elizabeth A., Strauss, Kevin A., Dunckley, Travis, Cardenas, Javier F., Melmed, Kara R., Wright, Courtney A., Liang, Winnie, Stafford, Phillip, Flynn, C. Robert, Morton, D. Holmes, Stephan, Dietrich A., de la Chapelle, Albert
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - genetics
Adult
Biological Sciences
Chromosome Mapping
Chromosomes
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Family Health
Female
Frameshift Mutation
Genes
Genetic loci
Genetics
Genome, Human
Genomes
Gonadal Dysgenesis - ethnology
Gonadal Dysgenesis - genetics
Humans
Infant
Infants
Male
Maple syrup urine disease
Nephrotic syndrome
Nuclear Proteins - genetics
Nuclear Proteins - physiology
Nucleosomes - genetics
Pedigree
Polymerase chain reaction
Sequencing
Sex-Determining Region Y Protein
SIDS
Sudden Infant Death - ethnology
Sudden Infant Death - genetics
Sudden infant death syndrome
Transcription Factors - genetics
Transcription Factors - physiology
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401194101