当前位置： SCI文献检索 > AMERICAN JOURNAL OF HUMAN GENETICS期刊下所有文献 > HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans.

HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans.

Abstract：

:The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other "spliceosomopathies" linked to variants that drive multi-system congenital defects and are found in hnRNPs.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Duijkers FA,McDonald A,Janssens GE,Lezzerini M,Jongejan A,van Koningsbruggen S,Leeuwenburgh-Pronk WG,Wlodarski MW,Moutton S,Tran-Mau-Them F,Thauvin-Robinet C,Faivre L,Monaghan KG,Smol T,Boute-Benejean O,Ladda RL,Sell SL,

doi

10.1016/j.ajhg.2019.03.024

subject

Has Abstract

pub_date

2019-06-06 00:00:00

pages

1040-1059

issue

6

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(19)30120-X

journal_volume

104

pub_type

杂志文章

相关文献

AMERICAN JOURNAL OF HUMAN GENETICS文献大全
  • TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita.

    abstract：:Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but approximately 60% of DC patients lack an identifiable mutation. With the very short telomer...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1016/j.ajhg.2007.10.004

    authors： Savage SA,Giri N,Baerlocher GM,Orr N,Lansdorp PM,Alter BP

    更新日期：2008-02-01 00:00:00

  • Mutations in DHDPSL are responsible for primary hyperoxaluria type III.

    abstract：:Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respect...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1016/j.ajhg.2010.07.023

    authors： Belostotsky R,Seboun E,Idelson GH,Milliner DS,Becker-Cohen R,Rinat C,Monico CG,Feinstein S,Ben-Shalom E,Magen D,Weissman I,Charon C,Frishberg Y

    更新日期：2010-09-10 00:00:00

  • A comparison of phasing algorithms for trios and unrelated individuals.

    abstract：:Knowledge of haplotype phase is valuable for many analysis methods in the study of disease, population, and evolutionary genetics. Considerable research effort has been devoted to the development of statistical and computational methods that infer haplotype phase from genotype data. Although a substantial number of su...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/500808

    authors： Marchini J,Cutler D,Patterson N,Stephens M,Eskin E,Halperin E,Lin S,Qin ZS,Munro HM,Abecasis GR,Donnelly P,International HapMap Consortium.

    更新日期：2006-03-01 00:00:00

  • Estimation of age and rate of increase of rare variants.

    abstract：:The problem considered is that of estimating the age or rate of increase of a variant on the basis of the present number of replicates observed in a population. In place of previous diffusion equation analyses of age probability distributions, the likelihood for the age is studied on the basis of a discrete branching ...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Thompson EA

    更新日期：1976-09-01 00:00:00

  • Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells.

    abstract：:Cells from persons with Bloom syndrome feature an elevated rate of sister-chromatid exchange (SCE). However, in some affected persons a minority of blood lymphocytes have a normal SCE rate. Persons who inherit the Bloom syndrome gene BLM identical by descent from a common ancestor very rarely exhibit this high-SCE/low...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Ellis NA,Lennon DJ,Proytcheva M,Alhadeff B,Henderson EE,German J

    更新日期：1995-11-01 00:00:00

  • Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism.

    abstract：:Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a gene...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/342732

    authors： Smalley SL,Kustanovich V,Minassian SL,Stone JL,Ogdie MN,McGough JJ,McCracken JT,MacPhie IL,Francks C,Fisher SE,Cantor RM,Monaco AP,Nelson SF

    更新日期：2002-10-01 00:00:00

  • cDNA cloning and chromosomal localization (4q11-13) of a gene for statherin, a regulator of calcium in saliva.

    abstract：:On the basis of the known amino acid sequence of statherin, a human salivary protein, mixed synthetic oligonucleotides were synthesized and used to screen a cDNA library constructed from human parotid-gland mRNA. A cDNA clone coding for statherin was isolated from this library and has been completely sequenced. The cD...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Sabatini LM,Carlock LR,Johnson GW,Azen EA

    更新日期：1987-12-01 00:00:00

  • Age-related somatic structural changes in the nuclear genome of human blood cells.

    abstract：:Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we desc...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1016/j.ajhg.2011.12.009

    authors： Forsberg LA,Rasi C,Razzaghian HR,Pakalapati G,Waite L,Thilbeault KS,Ronowicz A,Wineinger NE,Tiwari HK,Boomsma D,Westerman MP,Harris JR,Lyle R,Essand M,Eriksson F,Assimes TL,Iribarren C,Strachan E,O'Hanlon TP,Rider L

    更新日期：2012-02-10 00:00:00

  • The Expanding Landscape of Alternative Splicing Variation in Human Populations.

    abstract：:Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed...

    journal_title：American journal of human genetics

    pub_type： 杂志文章,评审

    doi：10.1016/j.ajhg.2017.11.002

    authors： Park E,Pan Z,Zhang Z,Lin L,Xing Y

    更新日期：2018-01-04 00:00:00

  • Allelic skewing of DNA methylation is widespread across the genome.

    abstract：:DNA methylation is assumed to be complementary on both alleles across the genome, although there are exceptions, notably in regions subject to genomic imprinting. We present a genome-wide survey of the degree of allelic skewing of DNA methylation with the aim of identifying previously unreported differentially methyla...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1016/j.ajhg.2010.01.014

    authors： Schalkwyk LC,Meaburn EL,Smith R,Dempster EL,Jeffries AR,Davies MN,Plomin R,Mill J

    更新日期：2010-02-12 00:00:00

  • A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence.

    abstract：:Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a metho...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1016/j.ajhg.2015.05.005

    authors： Lou H,Lu Y,Lu D,Fu R,Wang X,Feng Q,Wu S,Yang Y,Li S,Kang L,Guan Y,Hoh BP,Chung YJ,Jin L,Su B,Xu S

    更新日期：2015-07-02 00:00:00

  • TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways.

    abstract：:Steroid-resistant nephrotic syndrome (SRNS) is characterized by high-range proteinuria and most often focal and segmental glomerulosclerosis (FSGS). Identification of mutations in genes causing SRNS has improved our understanding of disease mechanisms and highlighted defects in the podocyte, a highly specialized glome...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1016/j.ajhg.2018.12.016

    authors： Dorval G,Kuzmuk V,Gribouval O,Welsh GI,Bierzynska A,Schmitt A,Miserey-Lenkei S,Koziell A,Haq S,Benmerah A,Mollet G,Boyer O,Saleem MA,Antignac C

    更新日期：2019-02-07 00:00:00

  • Combination of silver and fluorescent staining for metaphase chromosomes.

    abstract：:A convenient and reliable method for simulatneous visualization of silver staining (Ag-NOR) of the nucleolus organizers and fluorescent bandings in metaphase chromosomes is described. Studies employing this combined procedure on human chromosomes revealed that the Ag-NOR patterns may be characteristic for each chromos...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Lau YF,Pfeiffer RA,Arrighi FE,Hsu TC

    更新日期：1978-01-01 00:00:00

  • The phylogeography of Brazilian Y-chromosome lineages.

    abstract：:We examined DNA polymorphisms in the nonrecombining portion of the Y-chromosome to investigate the contribution of distinct patrilineages to the present-day white Brazilian population. Twelve unique-event polymorphisms were typed in 200 unrelated males from four geographical regions of Brazil and in 93 Portuguese male...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/316931

    authors： Carvalho-Silva DR,Santos FR,Rocha J,Pena SD

    更新日期：2001-01-01 00:00:00

  • Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.

    abstract：:Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogene...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/320588

    authors： Buxbaum JD,Silverman JM,Smith CJ,Kilifarski M,Reichert J,Hollander E,Lawlor BA,Fitzgerald M,Greenberg DA,Davis KL

    更新日期：2001-06-01 00:00:00

  • RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa.

    abstract：:We determined the mutation spectrum of the RP2 and RPGR genes in patients with X-linked retinitis pigmentosa (XLRP) and searched for correlations between categories of mutation and severity of disease. We screened 187 unrelated male patients for mutations, including 135 with a prior clinical diagnosis of XLRP, 11 with...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/379379

    authors： Sharon D,Sandberg MA,Rabe VW,Stillberger M,Dryja TP,Berson EL

    更新日期：2003-11-01 00:00:00

  • Chromosome 17q linkage studies of 18 Utah breast cancer kindreds.

    abstract：:In this paper we present linkage results from the analysis of 18 Utah breast cancer kindreds, for three 17q markers. Four kindreds had LOD scores greater than 1.0 for at least one of the marker loci. One of these kindreds has a LOD score of 6.07 with D17S579, and we believe it to be the most informative 17q family rep...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Goldgar DE,Cannon-Albright LA,Oliphant A,Ward JH,Linker G,Swensen J,Tran TD,Fields P,Uharriet P,Skolnick MH

    更新日期：1993-04-01 00:00:00

  • Combined use of biallelic and microsatellite Y-chromosome polymorphisms to infer affinities among African populations.

    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

    authors： Scozzari R,Cruciani F,Santolamazza P,Malaspina P,Torroni A,Sellitto D,Arredi B,Destro-Bisol G,De Stefano G,Rickards O,Martinez-Labarga C,Modiano D,Biondi G,Moral P,Olckers A,Wallace DC,Novelletto A

    更新日期：1999-09-01 00:00:00

  • Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21.3-q22.1.

    abstract：:Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locu...

    journal_title：American journal of human genetics

    pub_type： 杂志文章,评审

    doi：

    authors： Scherer SW,Poorkaj P,Allen T,Kim J,Geshuri D,Nunes M,Soder S,Stephens K,Pagon RA,Patton MA

    更新日期：1994-07-01 00:00:00

  • Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation.

    abstract：:CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogeni...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/500273

    authors： Lalani SR,Safiullah AM,Fernbach SD,Harutyunyan KG,Thaller C,Peterson LE,McPherson JD,Gibbs RA,White LD,Hefner M,Davenport SL,Graham JM,Bacino CA,Glass NL,Towbin JA,Craigen WJ,Neish SR,Lin AE,Belmont JW

    更新日期：2006-02-01 00:00:00

  • MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population.

    abstract：:Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome. We have previously reported a high incidence of microsatellite instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong Kong Chin...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/383591

    authors： Chan TL,Chan YW,Ho JW,Chan C,Chan AS,Chan E,Lam PW,Tse CW,Lee KC,Lau CW,Gwi E,Leung SY,Yuen ST

    更新日期：2004-05-01 00:00:00

  • Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement.

    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

    authors： Estrada-Cuzcano A,Neveling K,Kohl S,Banin E,Rotenstreich Y,Sharon D,Falik-Zaccai TC,Hipp S,Roepman R,Wissinger B,Letteboer SJ,Mans DA,Blokland EA,Kwint MP,Gijsen SJ,van Huet RA,Collin RW,Scheffer H,Veltman JA,Zrenne

    更新日期：2012-01-13 00:00:00

  • Parental inheritance and psychological disability in fragile X females.

    abstract：:Studies of adult female carriers of the fragile X chromosome indicate that certain psychological problems occur with a greater frequency and severity than expected. This study examines the association of parental origin of the fragile X chromosome and of fragility detected in the karyotype with measures of social, edu...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Reiss AL,Freund L,Vinogradov S,Hagerman R,Cronister A

    更新日期：1989-11-01 00:00:00

  • A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci.

    abstract：:Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there i...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：10.1086/375451

    authors： Fain PR,Gowan K,LaBerge GS,Alkhateeb A,Stetler GL,Talbert J,Bennett DC,Spritz RA

    更新日期：2003-06-01 00:00:00

  • A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD).

    abstract：:Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a serious and potentially fatal inherited defect in the beta-oxidation of fatty acids. Approximately 80% of patients with MCAD deficiency are homozygous for a single disease-causing mutation (G985). The remaining patients (except for a few cases worldwide) are c...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Andresen BS,Bross P,Jensen TG,Winter V,Knudsen I,Kølvraa S,Jensen UB,Bolund L,Duran M,Kim JJ

    更新日期：1993-09-01 00:00:00

  • Bloom syndrome and maternal uniparental disomy for chromosome 15.

    abstract：:Bloom syndrome (BS) is an autosomal recessive disorder characterized by increases in the frequency of sister-chromatid exchange and in the incidence of malignancy. Chromosome-transfer studies have shown the BS locus to map to chromosome 15q. This report describes a subject with features of both BS and Prader-Willi syn...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Woodage T,Prasad M,Dixon JW,Selby RE,Romain DR,Columbano-Green LM,Graham D,Rogan PK,Seip JR,Smith A

    更新日期：1994-07-01 00:00:00

  • Sex-chromosome pairing: evidence that the behavior of the pseudoautosomal region differs during male and female meiosis.

    abstract：:In humans, recombination in the pseudoautosomal region is approximately 10-fold higher in males than in females. This difference is thought to reflect the fact that, in females, there is opportunity for genetic exchange along the entire length of the X chromosome, resulting in a relative reduction in the likelihood of...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Hunt PA,LeMaire R

    更新日期：1992-06-01 00:00:00

  • A major locus for myoclonus-dystonia maps to chromosome 7q in eight families.

    abstract：:Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Klein C,Schilling K,Saunders-Pullman RJ,Garrels J,Breakefield XO,Brin MF,deLeon D,Doheny D,Fahn S,Fink JS,Forsgren L,Friedman J,Frucht S,Harris J,Holmgren G,Kis B,Kurlan R,Kyllerman M,Lang AE,Leung J,Raymond D,R

    更新日期：2000-11-01 00:00:00

  • Cigarette smoking and Down syndrome.

    abstract：:A matched case-control study of 100 mothers of Down syndrome children, 100 mothers of children with other defects (defect controls), and 100 mothers of children with no defects (normal controls) was carried out. All infants were born in upstate New York in 1980 and 1981. Matching was very close on maternal age for the...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Hook EB,Cross PK

    更新日期：1985-11-01 00:00:00

  • Dystrophin analysis in duchenne muscular dystrophy: use in fetal diagnosis and in genetic counseling.

    abstract：:In this report we describe the use of dystrophin analysis both in the diagnosis of Duchenne muscular dystrophy (DMD) in an aborted fetus and in genetic counseling. Our consultand's initial carrier risk, as based on family history and creatine kinase determinations, was calculated as 0.6%. DNA analysis of her family (a...

    journal_title：American journal of human genetics

    pub_type： 杂志文章

    doi：

    authors： Bieber FR,Hoffman EP,Amos JA

    更新日期：1989-09-01 00:00:00