Abstract:
:A modified alpha-N-acetylgalactosaminidase (NAGA) with alpha-galactosidase A (GLA)-like substrate specificity was designed on the basis of structural studies and was produced in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside. It retained the original NAGA's stability in plasma and N-glycans containing many mannose 6-phosphate (M6P) residues, which are advantageous for uptake by cells via M6P receptors. There was no immunological cross-reactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease recurrently treated with a recombinant GLA. The enzyme cleaved globotriaosylceramide (Gb3) accumulated in cultured fibroblasts from a patient with Fabry disease. Furthermore, like recombinant GLA proteins presently used for enzyme replacement therapy (ERT) for Fabry disease, the enzyme intravenously injected into Fabry model mice prevented Gb3 storage in the liver, kidneys, and heart and improved the pathological changes in these organs. Because this modified NAGA is hardly expected to cause an allergic reaction in Fabry disease patients, it is highly promising as a new and safe enzyme for ERT for Fabry disease.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Tajima Y,Kawashima I,Tsukimura T,Sugawara K,Kuroda M,Suzuki T,Togawa T,Chiba Y,Jigami Y,Ohno K,Fukushige T,Kanekura T,Itoh K,Ohashi T,Sakuraba Hdoi
10.1016/j.ajhg.2009.09.016subject
Has Abstractpub_date
2009-11-01 00:00:00pages
569-80issue
5eissn
0002-9297issn
1537-6605pii
S0002-9297(09)00412-1journal_volume
85pub_type
杂志文章abstract::Both the optimal marker density for genome scans in case-control association studies and the appropriate study design for the testing of candidate genes depend on the genomic pattern of linkage disequilibrium (LD). In this study, we provide the first conclusive demonstration that the diverse demographic histories of h...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/303083
更新日期:2000-10-01 00:00:00
abstract::Chromosomal aneuploidy is usually identified by cytogenetic methods. However, for some purposes it would be desirable to have an easier method of recognizing specific trisomies or monosomies. We have devised such an assay. It involves the simultaneous hybridization of two chromosome-specific DNA probes labeled with di...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1988-10-01 00:00:00
abstract::The lymphatic vasculature is essential for the recirculation of extracellular fluid, fat absorption, and immune function and as a route of tumor metastasis. The dissection of molecular mechanisms underlying lymphangiogenesis has been accelerated by the identification of tissue-specific lymphatic endothelial markers an...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2010.08.008
更新日期:2010-09-10 00:00:00
abstract::DNA length polymorphism in the 5'-flanking region of the human insulin gene has been reported by Bell et al. (1981), Rotwein et al. (1981), and Owerbach and Nerup (1982). Bgl I digestions of human DNA that have been hybridized to an insulin probe using the Southern technique shows that there are two distinct groups of...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1983-03-01 00:00:00
abstract::Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin alpha2 ch...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/301882
更新日期:1998-06-01 00:00:00
abstract::The distal portion of the short arm of the human X chromosome (Xp) exhibits many unique and interesting features. Distal Xp contains the pseudoautosomal region, a number of disease loci, and several cell-surface markers. Several genes in this area have also been observed to escape X-chromosomal inactivation. The chara...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1991-08-01 00:00:00
abstract::Aberrant gene expression underlies many human diseases. RNA polymerase II (Pol II) pausing is a key regulatory step in transcription. Here, we mapped the locations of RNA Pol II in normal human cells and found that RNA Pol II pauses in a consistent manner across individuals and cell types. At more than 1,000 genes inc...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.08.003
更新日期:2019-10-03 00:00:00
abstract::Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzi...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2020.12.007
更新日期:2021-01-04 00:00:00
abstract::Activating mutations in the genes for fibroblast growth factor receptors 1-3 (FGFR1-3) are responsible for a diverse group of skeletal disorders. In general, mutations in FGFR1 and FGFR2 cause the majority of syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutatio...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/427956
更新日期:2005-02-01 00:00:00
abstract::Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohor...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2019.05.015
更新日期:2019-07-03 00:00:00
abstract::Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emer...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2015.05.021
更新日期:2015-08-06 00:00:00
abstract::The association between normal alleles at the CTG repeat and two nearby polymorphisms in the myotonin protein kinase gene, the Alu insertion/deletion polymorphism and the myotonic dystrophy kinase (DMK)(G/T) intron 9/HinfI polymorphism, has been analyzed in South African Negroids, a population in which myotonic dystro...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-06-01 00:00:00
abstract::The homodimeric transmembrane receptor natriuretic peptide receptor B (NPR-B [also known as guanylate cyclase B, GC-B, and GUC2B]; gene name NPR2) produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP). CNP has previously been implicated in the regulation of skel...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/422013
更新日期:2004-07-01 00:00:00
abstract::Case-control studies compare marker-allele distributions in affected and unaffected individuals, and significant results suggest linkage but may simply reflect population structure. For markers with m alleles (m > or = 2), a McNemar-like statistic, I, estimates the level of population association between marker and di...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/339077
更新日期:2002-03-01 00:00:00
abstract::Joubert syndrome is a rare developmental defect of the cerebellar vermis, with autosomal recessive inheritance. The phenotype is highly variable and may include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental delay, and mental retardation. Even within sibships the phenotype may vary, makin...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302655
更新日期:1999-12-01 00:00:00
abstract::The mean and standard deviation of the first arrival time for a single mutant to reach a certain frequency and the mean age of a mutant persisting in a population have been studied using diffusion methods. These quantities are shown to be highly dependent on both the heterozygous effect and the population size. For pa...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-05-01 00:00:00
abstract::Proteoglycans are a major component of extracellular matrix and contribute to normal embryonic and postnatal development by ensuring tissue stability and signaling functions. We studied five patients with recessive joint dislocations and congenital heart defects, including bicuspid aortic valve (BAV) and aortic root d...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2011.05.021
更新日期:2011-07-15 00:00:00
abstract::Electrophoretic and quantitative studies reveal that 85% of Japanese carry an atypical liver alcohol dehydrogenase (ADH). The frequency of ADH polymorphism is identical with the reported frequency of alcohol sensitivity in the Japanese population. This identity in population frequencies points to a causative relations...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1975-11-01 00:00:00
abstract::Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosom...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302895
更新日期:2000-05-01 00:00:00
abstract::Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large num...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2015.12.011
更新日期:2016-02-04 00:00:00
abstract::The gene responsible for Krabbe disease, an autosomal recessive disorder caused by deficiency of galactocerebrosidase (GALC), was localized by multipoint linkage analysis on chromosome 14. Eight mapped dinucleotide repeat polymorphisms were tested for linkage to GALC. Two-point linkage analysis demonstrated close link...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1993-12-01 00:00:00
abstract::To define Y-chromosome haplotypes, we studied seven biallelic polymorphic sites. We combined data with those from four dinucleotide-repeat polymorphisms, to establish Y-chromosome compound superhaplotypes. Eight biallelic haplotypes that matched the dendrogram proposed by other investigators were identified in 762 Y c...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302538
更新日期:1999-09-01 00:00:00
abstract::We report here the characterization of a large Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness. In the absence of aminoglycosides, some matrilineal relatives in this family exhibited late-onset/progressive deafness, with a wide range of severity and age at onset. Notably, th...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/381133
更新日期:2004-01-01 00:00:00
abstract::Craniofrontonasal syndrome (CFNS) is an X-linked disorder that exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis, and additional minor malformations, but males are usually mildly affected with hypertelorism only. Despite this, males appe...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/504440
更新日期:2006-06-01 00:00:00
abstract::Moyamoya disease is characterized by bilateral stenosis and/or occlusion of the terminal portion of the internal carotid artery. Moyamoya disease is prevalent among patients <10 years of age. Although most cases appear to be sporadic, approximately 10% occur as familial cases. The incidence of familial cases has been ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302243
更新日期:1999-02-01 00:00:00
abstract::We measured the proportion of mutant mtDNA (mutation load) in 82 primary oocytes from a woman who harbored the A3243G mtDNA mutation. The frequency distribution of mutation load indicates that random drift is the principal mechanism that determines the level of mutant mtDNA within individual oocytes. ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/318190
更新日期:2001-02-01 00:00:00
abstract::Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2012.03.003
更新日期:2012-04-06 00:00:00
abstract::The data base of an ongoing population-based registry with multiple sources of ascertainment was used to estimate the present population load from genetic disease in more than 1 million consecutive live births. It was found that, before approximately age 25 years, greater than or equal to 53/1,000 live-born individual...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1988-05-01 00:00:00
abstract::A population-based study of hemophilia B mutations was conducted in the United Kingdom in order to construct a national confidential database of mutations and pedigrees to be used for the provision of carrier and prenatal diagnoses based on mutation detection. This allowed the direct estimate of overall (micro), male ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302651
更新日期:1999-12-01 00:00:00