NEW YORK (Reuters Health) - Mutations in a testis-specific gene are responsible for one form of sudden infant death syndrome (SIDS), according to a report in the July 19th PNAS Early Edition.
“We are beginning to sub-classify the generic term ‘Sudden Infant Death Syndrome’ into real disorders which have an underlying biological malfunction,” Dr. Dietrich A. Stephan from Translational Genomics Research Institute, Phoenix, Arizona told Reuters Health. “This will allow us to offer families hard diagnoses and thus counsel them on risks.”
SIDS with dysgenesis of the testes affects infants from the Belleville Amish community in southeastern Pennsylvania. Dr. Stephan and colleagues used high-density single-nucleotide polymorphism genotyping arrays to map the disease locus in 4 individuals with the condition and their parents from 3 sibships to a region on chromosome 6q22.1-q22.31. Two genes within that region were considered possible candidates based on sequence homology to the testis-specific gene TSPY.
Complete sequencing of one of the genes, TSPYL, in an affected individual identified a homozygous insertion between bases 457 and 458 (457_458insG), which prematurely truncated the protein at codon 169, the authors report.
Subsequent sequencing of all 42 individuals in the SIDS with dysgenesis of the testes syndrome pedigree revealed that all affected individuals were homozygous for the change, all parents of affected individuals were heterozygous for the mutation, and no unaffected siblings were homozygous for the change.
The mutation was not found in any Lancaster County Old Order Amish tested, the researchers note, but 4 heterozygotes were detected out of 16 chromosomes tested from the Mifflin and Juniata County Old Order Amish.
According to the investigators, the truncated TSPYL showed inappropriate subcellular targeting in an in vitro assay, further suggesting its role in causing SIDS with dysgenesis of the testes syndrome. Sequencing of the second gene candidate, TSPYL4, identified no coding variants.
“We do know that TSPYL is turned on at very specific times during embryonic brain and reproductive system development and likely mediates waves of gene regulation crucial for development of the male reproductive system and the autonomic nervous system functions,” Dr. Stephan said. “We are developing antibodies against this protein which will be used for immunohistochemistry on autopsy specimens from these infants to characterize the exact developmental brain anomalies resulting from TSPYL loss and culminating in death of the infant.”
“At this time we have no available therapeutic, but we hope that as our understanding of the disease grows we will find inroads into saving these infants,” Dr. Stephan said. “Therapeutic development is most effective when it is predicated on an understanding of the fundamental pathogenesis of the disease - which we have offered here as a first step.”
“We do know that molecular diagnostics in at risk couples, coupled with genetic counseling, can reduce the incidence of lethal disorders,” Dr. Stephan concluded. “Early diagnostics in the infant should be performed if the infant presents with a cry similar to that of a goat or abnormal breathing or heart rate.”
Source: PNAS 2004. [ Google search on this article ]
MeSH Headings:Gonadal DysgenesisCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
