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.
The analysis of single nucleotide polymorphisms (SNPs) is increasingly utilizedto investigate the genetic causes of complex human diseases. Here we present a high-throughput genotyping platform that uses a one-primer assay to genotype over 10,000 SNPs per individual on a single oligonucleotide array. This approach uses restriction digestion to fractionate the genome, followed by amplification of a specific fractionated subset of the genome. The resulting reduction in genome complexity enables al...
Genetic studies aimed at understanding the molecular basis of complex human phenotypes require the genotyping of many thousands of single-nucleotide polymorphisms (SNPs) across large numbers of individuals1. Public efforts have so far identified over two million common human SNPs2; however, the scoring of these SNPs is labor-intensive and requires a substantial amount of automation. Here we describe a simple but effective approach, termed whole-genome sampling analysis (WGSA), for genotyping tho...
Last. Matthew Guille(University of Portsmouth)H-Index: 19
view all 9 authors...
Nucleosome assembly proteins have been identified in all eukaryotic species investigated to date and their suggested roles include histone shuttle, histone acceptor during transcriptional chromatin remodelling and cell cycle regulator. To examine the role of these proteins during early development we have isolated the cDNA encoding Xenopus NAP1L, raised an antibody against recombinant xNAP1L and examined the expression pattern of this mRNA and protein. Expression in adults is predominantly in ov...
This article presents a brief description of the reflex mechanisms responsible for cough and bronchospasm, and identifies several potential mechanisms by which gastroesophageal reflux (GER) may precipitate these reflexes. Airway and esophageal reflexes related to various mechanoreceptors and chemoreceptors have been elucidated, primarily in animal studies. Central nervous system (CNS) reflex pathways as well as local axon reflexes may each contribute to the pathogenesis of both asthma and GER di...
The Old Order Mennonites of southeastern Pennsylvania are a religious isolate with origins in 16th-century Switzerland. The Swiss Mennonites immigrated to Pennsylvania over a 50-year period in the early 18th century. The history of this population in the United States provides insight into the increased incidence of several genetic diseases, most notably maple syrup urine disease (MSUD), Hirschsprung disease (HSCR), and congenital nephrotic syndrome. A comparison between the Old Order Mennonites...
Import of core histones into the nucleus is a prerequisite for their deposition onto DNA and the assembly of chromatin. Here we demonstrate that nucleosome assembly protein 1 (Nap1p), a protein previously implicated in the deposition of histones H2A and H2B, is also involved in the transport of these two histones. We demonstrate that Nap1p can bind directly to Kap114p, the primary karyopherin/importin responsible for the nuclear import of H2A and H2B. Nap1p also serves as a bridge between Kap114...
#1Mark J. Daly(MIT: Massachusetts Institute of Technology)H-Index: 213
#2John D. Rioux(MIT: Massachusetts Institute of Technology)H-Index: 93
Last. Eric S. Lander(MIT: Massachusetts Institute of Technology)H-Index: 294
view all 5 authors...
Linkage disequilibrium (LD) analysis is traditionally based on individual genetic markers and often yields an erratic, non-monotonic picture, because the power to detect allelic associations depends on specific properties of each marker, such as frequency and population history. Ideally, LD analysis should be based directly on the underlying haplotype structure of the human genome, but this structure has remained poorly understood. Here we report a high-resolution analysis of the haplotype struc...
The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality in the United States today, despite a dramatic 38% decrease in incidence due to a national risk reduction campaign advocating the supine sleep position. Our research in SIDS brainstems, beginning in 1985 and involving a single, large dataset, has become increasingly focused upon a specific neurotransmitter (serotonin) and specific territories (ventral medulla and regions of the medullary reticular forma...
Uridine-diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile. Bilirubin-UGT1 (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin. Lesions in the gene encoding bilirubin-UGT1, lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler-Najjar syndrome...
The possibility of reversible cardiac asystoly due to paroxysmal vagal overactivity (VO) has been well studied, first in adults, then in children, and finally in breath-holding spells. Few studies dea
Last. Heng Wang(Boston Children's Hospital)H-Index: 13
view all 4 authors...
A decade has passed since transmembrane coiled-coil domains 1 (TMCO1) defect syndrome was identified in 11 undiagnosed patients within the Old Order Amish of Northeastern Ohio – a disorder characterized by a distinctive craniofacial dysmorphism, skeletal anomalies and global developmental delay. 27 patients, from diverse ethnic groups, have been reported with pathogenic TMCO1 variants now recognized to cause cerebrofaciothoracic dysplasia (CFTD). The implication of previously uncharacterized TMC...
Last. Ingrid A. Holm(Boston Children's Hospital)H-Index: 43
view all 4 authors...
Sudden Infant Death syndrome (SIDS) is a diagnosis of exclusion. Decades of research have made steady gains in understanding plausible mechanisms of terminal events. Current evidence suggests SIDS includes heterogeneous biological conditions, such as metabolic, cardiac, neurologic, respiratory, and infectious conditions. Here we review genetic studies that address each of these areas in SIDS cases and cohorts, providing a broad view of the genetic underpinnings of this devastating phenomenon. Th...
Last. Su-Ren Chen(BNU: Beijing Normal University)H-Index: 16
view all 3 authors...
Background Infertility is a major issue in human reproductive health, affecting an estimated 15% of couples worldwide. Infertility can result from disorders of sex development (DSD) or from reproductive endocrine disorders (REDs) with onset in infancy, early childhood or adolescence. Male infertility, accounting for roughly half of all infertility cases, generally manifests as decreased sperm count (azoospermia or oligozoospermia), attenuated sperm motility (asthenozoospermia) or a higher propor...
#2Michela Di Michele(ENSCM: École nationale supérieure de chimie de Montpellier)
Last. Kathleen Freson(Katholieke Universiteit Leuven)H-Index: 35
view all 11 authors...
We describe a lethal combined nervous and reproductive systems disease in three affected siblings of a consanguineous family. The phenotype was characterized by visceroautonomic dysfunction (neonatal bradycardia/apnea, feeding problems, hyperactive startle reflex), severe postnatal progressive neurological abnormalities (including abnormal neonatal cry, hypotonia, epilepsy, polyneuropathy, cerebral gray matter atrophy), visual impairment, testicular dysgenesis in males, and sudden death at infan...
Histone chaperones are a class of proteins that bind and transport histones, preventing their chaotic aggregation when forming nucleosomes. Histone chaperones of the NAP (Nucleosome Assembly Protein) family contain a highly conserved central NAP domain, which is necessary for histone binding and nucleosome assembly. They are an essential component in creating and maintaining the eukaryotic chromatin dynamics on which the transcription of many genes depends. The review considers the NAP family of...
Objective To determine the importance of testis-specific, Y-encoded-like 1 (TSPYL1) in survival and male factor fertility in mice. Design Experimental prospective study. Setting Research laboratories in a university medical faculty. Animals We generated Tspyl1 knockout (KO) mouse lines by CRISPR/Cas9. The lines were maintained by pairing heterozygous mice to provide wild-type control and KO males for comparison. Intervention(s) None. Main Outcome Measure(s) Mendelian ratio, body and testis weigh...
Sudden Infant Death with Dysgenesis of the Testes syndrome (SIDDT) is a very rare condition associated with biallelic pathogenic variants in the TSPYL1 gene first reported in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction, and is uniformly fatal before the age of 12 months. There were previously 21 reported cases of SIDDT in the literature, all from nine Old Order Amish families published in a single paper. In this rep...
#1Romina P Grinspon(CONICET: National Scientific and Technical Research Council)H-Index: 17
#2Ignacio Bergadá(CONICET: National Scientific and Technical Research Council)H-Index: 21
Last. Rodolfo Rey(UBA: University of Buenos Aires)H-Index: 63
view all 3 authors...
Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal and/or internal/external genital sex. In XY individuals, the process of fetal sex differentiation can be disrupted at the stage of gonadal differentiation, resulting in gonadal dysgenesis, a form of early fetal-onset primary hypogonadism characterized by insufficient androgen and anti-Mullerian (AMH) hormone production, which leads to the development of ambiguous or f...
#2Cynthia Vied(FSU: Florida State University)H-Index: 11
Last. Jose R. Pinto(FSU: Florida State University)H-Index: 22
view all 6 authors...
Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in both sexes. Among the susceptible genes, TNNC1-encoding cardiac troponin C (cTnC)-causes a substantial HCM phenotype in mice. Mice bearing an HCM-associated cTnC-A8V point mutation exhibited a signif...
Last. Sonia Grover(University of Melbourne)H-Index: 32
view all 3 authors...
DSD, with 46,XY chromosomal complement, comprise a heterogeneous group of conditions, where either the hormones associated with virilisation (androgens) are not produced, or the target organs are unable to respond in a typical manner. Important causes to consider in these individuals are gonadal dysgenesis, variations in androgen synthesis and androgen insensitivity syndrome (AIS)—partial or complete. However, the precise nature of many 46,XY DSD cannot be diagnosed at a molecular level. Improve...