Abstract:
:Inherited retinal dystrophies are a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. We analyzed a large five-generation pedigree with early-onset recessive retinal degeneration to identify the causative mutation. Linkage analysis and homozygosity mapping combined with exome sequencing were carried out to map the disease locus and identify the p.G178R mutation in the asparaginase like-1 gene (ASRGL1), segregating with the retinal dystrophy phenotype in the study pedigree. ASRGL1 encodes an enzyme that catalyzes the hydrolysis of L-asparagine and isoaspartyl-peptides. Studies on the ASRGL1 expressed in Escherichia coli and transiently transfected mammalian cells indicated that the p.G178R mutation impairs the autocatalytic processing of this enzyme resulting in the loss of functional ASRGL1 and leaving the inactive precursor protein as a destabilized and aggregation-prone protein. A zebrafish model overexpressing the mutant hASRGL1 developed retinal abnormalities and loss of cone photoreceptors. Our studies suggest that the p.G178R mutation in ASRGL1 leads to photoreceptor degeneration resulting in progressive vision loss.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Biswas P,Chavali VR,Agnello G,Stone E,Chakarova C,Duncan JL,Kannabiran C,Homsher M,Bhattacharya SS,Naeem MA,Kimchi A,Sharon D,Iwata T,Riazuddin S,Reddy GB,Hejtmancik JF,Georgiou G,Riazuddin SA,Ayyagari Rdoi
10.1093/hmg/ddw113subject
Has Abstractpub_date
2016-06-15 00:00:00pages
2483-2497issue
12eissn
0964-6906issn
1460-2083pii
ddw113journal_volume
25pub_type
杂志文章abstract::Failures in neurotrophic support and signalling play key roles in Alzheimer's disease (AD) pathogenesis. We previously demonstrated that downregulation of the neurotrophin effector Kinase D interacting substrate (Kidins220) by excitotoxicity and cerebral ischaemia contributed to neuronal death. This downregulation, tr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds446
更新日期:2013-02-01 00:00:00
abstract::Fragile X syndrome is the most frequent cause of heritable mental retardation. Most patients have a mutation in the 5' untranslated region of the FMR1 gene, consisting of the amplification of a polymorphic (CGG)nrepeat sequence, and cytogenetically express the folate-sensitive fragile site FRAXA in Xq27.3. Fragile X p...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.1.109
更新日期:1998-01-01 00:00:00
abstract::Evidence of the effects of genetic risk score (GRS) on secondary prevention is scarce and mixed. We investigated whether coronary artery disease (CAD) susceptible loci can be used to predict the risk of major adverse cardiovascular events (MACEs) in a cohort with acute coronary syndromes (ACSs). A total of 1667 patien...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa025
更新日期:2020-04-15 00:00:00
abstract::Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt015
更新日期:2013-04-15 00:00:00
abstract::Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some resid...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt217
更新日期:2013-09-15 00:00:00
abstract::Rheumatoid arthritis (RA) is the commonest chronic, systemic, inflammatory disorder affecting ∼1% of the world population. It has a strong genetic component and a growing number of associated genes have been discovered in genome-wide association studies (GWAS), which nevertheless only account for 23% of the total gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr248
更新日期:2011-09-01 00:00:00
abstract::To assess the relationship between the genotype and phenotype of adult CF patients we have selected from a group of 512 CF patients attending centres in France, all these of greater than 35 years. We have analysed the entire coding sequence of their CFTR genes. The complete genotype was determined in 7 of the 8 patien...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.10.1557
更新日期:1993-10-01 00:00:00
abstract::The presence of an extra Y chromosome in males is a relatively common occurrence, the 47,XYY karyotype being found in approximately 1 in 1000 male births. The error of disjunction must occur either during paternal meiosis II or as a post-zygotic mitotic error, both of which are rare events for other chromosomes. It is...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.12.2205
更新日期:1999-11-01 00:00:00
abstract::Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified gen...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu044
更新日期:2014-06-15 00:00:00
abstract::Many congenital myasthenic syndromes (CMS) are associated with mutations in the genes encoding the acetylcholine receptor (AChR), an oligomeric protein with the structure alpha(2)betadelta epsilon. AChR deficiency is frequently due to homozygous or heteroallelic mutations in the AChR epsilon subunit, most of which cau...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.24.3087
更新日期:2002-11-15 00:00:00
abstract::Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.9.1119
更新日期:2002-05-01 00:00:00
abstract::Mutations in S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) cause a recessively inherited multisystemic disorder whose main features are retinal degeneration and intellectual disability. SCAPER, originally identified as a cell cycle regulator, was also suggested to be a ciliary protein. Beca...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa113
更新日期:2020-08-03 00:00:00
abstract::Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional survival motor neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses on modulating the expression of a partially functioning copy gene, SMN2, which is reta...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn426
更新日期:2009-03-15 00:00:00
abstract::The purpose of this study was to determine whether thrombospondin (TSP)-1 promotes macrophage activity and disease progression in dysferlinopathy. First, we found that levels of TSP-1 are elevated in blood of non-ambulant dysferlinopathy patients compared with ambulant patients and healthy controls, supporting the ide...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx378
更新日期:2017-12-15 00:00:00
abstract::The intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes mediates ciliary protein trafficking. Mutations in the genes encoding the six subunits of the IFT-A complex (IFT43, IFT121, IFT122, IFT139, IFT140, and IFT144) are known to cause skeletal ciliopathies, including cranioectodermal dysp...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx421
更新日期:2018-02-01 00:00:00
abstract::Andersen's syndrome (AS) is a rare and dominantly inherited pathology, linked to the inwardly rectifying potassium channel Kir2.1. AS patients exhibit a triad of symptoms that include periodic paralysis, cardiac dysrhythmia and bone malformations. Some progress has been made in understanding the contribution of the Ki...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu462
更新日期:2015-01-15 00:00:00
abstract::A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from i...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.4.751
更新日期:1998-04-01 00:00:00
abstract::The comparison of several statistical methods currently used for detection of differentially expressed genes was attempted both by a simulation approach and by the analysis of data sets of human expressed sequence tags, obtained from UniGene. In the simulated mixed case, mimicking a situation close to reality, the gen...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.19.2133
更新日期:2001-09-15 00:00:00
abstract::Despite extensive progress in Huntington's disease (HD) research, very little is known about the association of epigenetic variation and HD pathogenesis in human brain tissues. Moreover, its contribution to the tissue-specific transcriptional regulation of the huntingtin gene (HTT), in which HTT expression levels are ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw076
更新日期:2016-05-15 00:00:00
abstract::Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of N...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.24.2751
更新日期:2001-11-15 00:00:00
abstract::Osteoarthritis (OA) is a common, painful and debilitating disease of articulating joints resulting from the age-associated loss of cartilage. Well-powered genetic studies have identified a number of DNA polymorphisms that are associated with OA susceptibility. Like most complex trait loci, these OA loci are thought to...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv433
更新日期:2015-12-20 00:00:00
abstract::An association between the 19q13.2 chromosomal region and Alzheimer's disease (AD) has been reported in AD families and for sporadic AD. Recent observations provide evidence that the epsilon 4 allele of the apolipoprotein E gene (APOE), located in this region, is a risk factor for late-onset AD. Within this region, ot...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.4.569
更新日期:1994-04-01 00:00:00
abstract::Sarcomeric α-actinins (α-actinin-2 and -3) are a major component of the Z-disk in skeletal muscle, where they crosslink actin and other structural proteins to maintain an ordered myofibrillar array. Homozygosity for the common null polymorphism (R577X) in ACTN3 results in the absence of fast fiber-specific α-actinin-3...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr196
更新日期:2011-08-01 00:00:00
abstract::A recurrent t(9;22) (q22;q12) chromosome translocation has been described in extraskeletal myxoid chondrosarcoma (EMC). Fluorescent in situ hybridization experiments performed on one EMC tumour indicated that the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant EWS transcr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.12.2219
更新日期:1995-12-01 00:00:00
abstract::Formation of protein aggregates is the hallmark of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and frontotemporal dementia. Many ubiquitin-associated proteins are recruited to protein aggregates, such as sequestosome 1/p62 (p62), parkin, and cereblon (CRBN). However, the roles of thes...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx433
更新日期:2018-02-15 00:00:00
abstract::alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a com...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.12.1953
更新日期:1998-11-01 00:00:00
abstract::Fragile X syndrome, a common form of inherited mental retardation, is caused by loss of the fragile X mental retardation protein (FMRP). As a selective RNA-binding protein, FMRP is localized predominately in cytoplasm, where it regulates translational control. However, there is a small portion of FMRP present in the n...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu241
更新日期:2014-10-01 00:00:00
abstract::Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.10.1495
更新日期:2000-06-12 00:00:00
abstract::Meiotic crossovers in the human genome cluster into highly localized hotspots identifiable indirectly from patterns of DNA diversity and directly by high-resolution sperm typing. Little is known about factors that control hotspot activity and the apparently rapid turnover of hotspots during recent evolution. Clues can...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl063
更新日期:2006-05-01 00:00:00
abstract::Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was pe...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl447
更新日期:2007-02-01 00:00:00