Abstract:
:Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss-of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome-wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(∗)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(∗)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Li M,Cheng R,Liang J,Yan H,Zhang H,Yang L,Li C,Jiao Q,Lu Z,He J,Ji J,Shen Z,Li C,Hao F,Yu H,Yao Zdoi
10.1016/j.ajhg.2013.04.022subject
Has Abstractpub_date
2013-06-06 00:00:00pages
895-903issue
6eissn
0002-9297issn
1537-6605pii
S0002-9297(13)00209-7journal_volume
92pub_type
杂志文章abstract::The gene that is involved in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease--CLN3--has been localized to 16p12, and the mutation shows a strong association with alleles of microsatellite markers D16S298, D16S299, and D16S288. Recently, haplotype analysis of a Batten patient from a consanguineous rel...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-03-01 00:00:00
abstract::Age at onset of motor symptoms was collected on 611 persons affected with Huntington disease (HD) among 3,201 persons "at risk" in 108 kindreds. Life-table estimates correcting for truncated intervals of observation (censoring) produced a median age at onset 5 years older than the observed mean. Risk estimates of HD o...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1988-11-01 00:00:00
abstract::Human neuroblastoma cells often are monosomic for the distal portion of 1p (1p36). We report that the deleted 1p material in cells of neuroblastoma lines is preferentially replaced by material from chromosome 17, resulting from an unbalanced 1;17 translocation. Chromosome 17 often acquires instability, followed by the...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1994-08-01 00:00:00
abstract::Comparisons are presented of the ages of onset of 20 cases of hereditary medullary carcinoma of the thyroid (MCT) and of 22 sporadic cases of this same type of cancer. These data are compatible with what might be expected by the two-mutational-event theory of the initiation of cancer postulated by Knudson. It had been...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1979-11-01 00:00:00
abstract::Dermal fibroblasts from most individuals with osteogenesis imperfecta (OI) type I produce about half the normal amount of type I procollagen, as a result of decreased synthesis of one of its constituent chains, pro alpha 1 (I). To test the hypothesis that decreased synthesis of pro alpha (I) chains results from mutati...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1992-09-01 00:00:00
abstract::Genetic and environmental influences on systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MBP) were examined in 371 French-Canadian families by using path analysis. Familial environment was estimated with environmental indices constructed from as many as 14 (of a pool of ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1989-08-01 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
abstract::Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/518720
更新日期:2007-07-01 00:00:00
abstract::Cellular DNAs from a panel of 20 unrelated individuals were screened for restriction fragment length polymorphisms (RFLP) with a DNA probe containing the first exon of the proopiomelanocortin gene (POMC), which has been assigned to chromosome 2p23-25. Digestion with the restriction endonuclease Sst 1 revealed a high f...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1983-11-01 00:00:00
abstract::The maximum-likelihood-binomial (MLB) method, based on the binomial distribution of parental marker alleles among affected offspring, recently was shown to provide promising results by two-point linkage analysis of affected-sibship data. In this article, we extend the MLB method to multipoint linkage analysis, using t...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/301958
更新日期:1998-08-01 00:00:00
abstract::We report the development and validation of experimental methods, study designs, and analysis software for pooling-based genomewide association (GWA) studies that use high-throughput single-nucleotide-polymorphism (SNP) genotyping microarrays. We first describe a theoretical framework for establishing the effectivenes...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/510686
更新日期:2007-01-01 00:00:00
abstract::A novel type IV collagen, alpha 3(IV), has recently been identified in human and bovine basement membranes. Here we describe the cloning and sequencing of a cDNA encoding 218 residues of the NC1 domain of the human alpha 3(IV) chain. Of interest is the possible role of abnormalities of the alpha 3(IV) chain in Alport ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1991-09-01 00:00:00
abstract::Duplications of proximal 15q have been found in individuals with autistic disorder (AD) and varying degrees of mental retardation. Often these abnormalities take the form of a supernumerary inverted duplicated chromosome 15, more properly described as an isodicentric chromosome 15, or idic(15). However, intrachromosom...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1997-04-01 00:00:00
abstract::The extent to which variants in the protein-coding sequence of genes contribute to risk of rheumatoid arthritis (RA) is unknown. In this study, we addressed this issue by deep exon sequencing and large-scale genotyping of 25 biological candidate genes located within RA risk loci discovered by genome-wide association s...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2012.11.012
更新日期:2013-01-10 00:00:00
abstract::We describe a new user-intense-learning experience that incorporates the teaching of clinical and research applications of human genetics in biochemistry while training first-year medical students to develop skills in computer access to the literature. Human genetics was incorporated into the biochemistry curriculum b...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1989-04-01 00:00:00
abstract::The purpose of this study was to characterize the mutant enzyme in nine patients with gyrate atrophy of the choroid and retina associated with ornithine aminotransferase (OAT) deficiency, to elucidate the mechanism of response to pyridoxine in four pyridoxine-responsive patients, and to determine the extent of genetic...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1989-03-01 00:00:00
abstract::We report the transmission of HLA haplotypes and Gm allotypes in 97 members of a single kindred containing 257 individuals, 45 of whom were determined by clinical examination, autopsy, or historical data to have had Alzheimer disease (AD). Extensive inbreeding suggests that more than one gene may contribute to suscept...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1983-05-01 00:00:00
abstract::Genetic loci for X-linked retinitis pigmentosa (XLRP) have been mapped between Xp11.22 and Xp22.13 (RP2, RP3, RP6, and RP15). The RP3 gene, which is responsible for the predominant form of XLRP in most Caucasian populations, has been localized to Xp21.1 by linkage analysis and the map positions of chromosomal deletion...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1996-07-01 00:00:00
abstract::Catecholamine-induced polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress. Two modes of inheritance have been described: autosomal dominant and autosomal recessive. Mutations in the ryanodine receptor 2 gene ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/324565
更新日期:2001-12-01 00:00:00
abstract::In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits. Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies. Two patients were diagnosed w...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/341327
更新日期:2002-07-01 00:00:00
abstract::The genetically inactive, late-replicating human female X chromosome can be effectively distinguished from its more active, earlier-replicating homologue, when cells are grown according to the appropriate BrdU-33258 Hoechst protocol. Results obtained from a fluorescence analysis of DNA replication in X chromosomes are...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1976-05-01 00:00:00
abstract::Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large c...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2018.02.010
更新日期:2018-04-05 00:00:00
abstract::Genetic risks are usually computed under the assumption that genetic parameters, such as the recombination fraction, are known without error. Uncertainty in the estimates of these parameters must translate into uncertainty regarding the risk. To allow for uncertainties in parameter values, one may employ Bayesian tech...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1994-05-01 00:00:00
abstract::Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2011.11.015
更新日期:2012-01-13 00:00:00
abstract::Apolipoprotein J (apo J) is a newly identified member of a growing family of proteins associated with various lipoprotein particles. Apo J is a glycoprotein which exists in the plasma associated with high-density lipoprotein subfractions which also contain apo A-I and cholesteryl ester transfer protein (CETP). We have...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1991-12-01 00:00:00
abstract::Alpha-globin gene cluster haplotypes were determined in Southern African San and negroid populations. Significant differences (P less than .01) between the two groups were found at three of the nine loci in the cluster. The most striking difference, however, was the relatively low level of variation found in the San (...
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::Most sporadic cases of retinoblastoma, malignant eye tumor of children, may require the identification of a mutation of the retinoblastoma gene (RB1 gene) for precise genetic counseling. We established a mutation detection system of and screened for the RB1 gene mutation in 24 patients with retinoblastoma--12 bilatera...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1994-05-01 00:00:00
abstract::Several spin-label electron paramagnetic resonance (EPR) studies of red cell membranes appear to show abnormalities in some Huntington disease (HD) patients, but not in others. Both studies measure the W/S ratios, presumably under similar conditions, but have different results. We have studied the W/S ratio in some de...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1982-05-01 00:00:00
abstract::An astonishing amount of behavioral variation is captured within the more than 350 breeds of dog recognized worldwide. Inherent in observations of dog behavior is the notion that much of what is observed is breed specific and will persist, even in the absence of training or motivation. Thus, herding, pointing, trackin...
journal_title:American journal of human genetics
pub_type: 杂志文章,评审
doi:10.1016/j.ajhg.2007.12.001
更新日期:2008-01-01 00:00:00
abstract::Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis pigmentosa. The mutation that most commonly causes Usher syndrome type IIa is a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identifie...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/321269
更新日期:2001-07-01 00:00:00