Browsing by Subject "Genetic Diseases, Inborn"

Now showing 1 - 3 of 3

Open Access
A Genocentric Approach to Discovery of Mendelian Disorders.
(American journal of human genetics, 2019-11) Hansen, Adam W; Murugan, Mullai; Li, He; Khayat, Michael M; Wang, Liwen; Rosenfeld, Jill; Andrews, B Kim; Jhangiani, Shalini N; Coban Akdemir, Zeynep H; Sedlazeck, Fritz J; Ashley-Koch, Allison E; Liu, Pengfei; Muzny, Donna M; Task Force for Neonatal Genomics; Davis, Erica E; Katsanis, Nicholas; Sabo, Aniko; Posey, Jennifer E; Yang, Yaping; Wangler, Michael F; Eng, Christine M; Sutton, V Reid; Lupski, James R; Boerwinkle, Eric; Gibbs, Richard A
The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.
Open Access
Cell therapy for diverse central nervous system disorders: inherited metabolic diseases and autism.
(Pediatric research, 2018-01) Sun, Jessica M; Kurtzberg, Joanne
The concept of utilizing human cells for the treatment of medical conditions is not new. In its simplest form, blood product transfusion as treatment of severe hemorrhage has been practiced since the 1800s. The advent of hematopoietic stem cell transplantation (HSCT) began with the development of bone marrow transplantation for hematological malignancies in the mid-1900s and is now the standard of care for many hematological disorders. In the past few decades, HSCT has expanded to additional sources of donor cells, a wider range of indications, and the development of novel cell products. This trajectory has sparked a rapidly growing interest in the pursuit of innovative cell therapies to treat presently incurable diseases, including neurological conditions. HSCT is currently an established therapy for certain neurologically devastating inherited metabolic diseases, in which engrafting donor cells provide lifelong enzyme replacement that prevents neurological deterioration and significantly extends the lives of affected children. Knowledge gained from the treatment of these rare conditions has led to refinement of the indications and timing of HSCT, the study of additional cellular products and techniques to address its limitations, and the investigation of cellular therapies without transplantation to treat more common neurological conditions, such as autism spectrum disorder.
Open Access
Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.
(J Clin Invest, 2010-03) O'Toole, JF; Liu, Y; Davis, EE; Westlake, CJ; Attanasio, M; Otto, EA; Seelow, D; Nurnberg, G; Becker, C; Nuutinen, M; Kärppä, M; Ignatius, J; Uusimaa, J; Pakanen, S; Jaakkola, E; van den Heuvel, LP; Fehrenbach, H; Wiggins, R; Goyal, M; Zhou, W; Wolf, MT; Wise, E; Helou, J; Allen, SJ; Murga Zamalloa, CA; Ashraf, S; Chaki, M; Heeringa, S; Chernin, G; Hoskins, BE; Chaib, H; Gleeson, J; Kusakabe, T; Suzuki, T; Isaac, RE; Quarmby, LM; Tennant, B; Fujioka, H; Tuominen, H; Hassinen, I; Lohi, H; van Houten, JL; Rotig, A; Sayer, JA; Rolinski, B; Freisinger, P; Madhavan, SM; Herzer, M; Madignier, F; Prokisch, H; Nurnberg, P; Jackson, PK; Jackson, P; Khanna, H; Katsanis, N; Hildebrandt, F
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.