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 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.
Puffenberger
Erik G
EG
Clinic for Special Children, Strasburg, PA 17579, USA.
Hu-Lince
Diane
D
Parod
Jennifer M
JM
Craig
David W
DW
Dobrin
Seth E
SE
Conway
Andrew R
AR
Donarum
Elizabeth A
EA
Strauss
Kevin A
KA
Dunckley
Travis
T
Cardenas
Javier F
JF
Melmed
Kara R
KR
Wright
Courtney A
CA
Liang
Winnie
W
Stafford
Phillip
P
Flynn
C Robert
CR
Morton
D Holmes
DH
Stephan
Dietrich A
DA
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000328:Adult; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D015894:Genome, Human; D006059:Gonadal Dysgenesis / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D009707:Nucleosomes / Q000235:genetics; D010375:Pedigree; D051876:Sex-Determining Region Y Protein; D013398:Sudden Infant Death / Q000208:ethnology / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D009707:Nucleosomes; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors