Functional characterization of splicing and ligand-binding domain variants in the LDL receptor.


:Familial hypercholesterolemia (FH) is an autosomal dominant disorder mostly caused by mutations in the LDLR gene. Although the detection of functional mutations in the LDLR gene provides an unequivocal diagnosis of the FH condition, there are many variants whose pathogenicity is still unknown. The aims of this study were to set up a rapid method to determine the effect of LDLR mutations, thereby providing an accurate diagnosis of FH, and to functionally characterize six LDLR mutations detected at high frequency by the LIPOchip(®) platform (Progenika Biopharma, Spain) in the Spanish population. LDLR expression and activity were analyzed by one-single-step flow cytometry assay and confocal microscopy. Splicing effects were determined by sequencing reverse transcription polymerase chain reaction products. The analysis of three heterozygous variants with a single point mutation within the low-density lipoprotein binding domain allowed us to classify the c.806G>A variant as nonpathogenic, and c.862G>A and c.895G>A variants as causative of FH. The results obtained for three variants affecting donor splice sites of the LDLR mRNA, c.313+2dupT, c.1186+5G>A, and c.1845+1G>C, demonstrated that these mutations are pathogenic. These results expand our knowledge of mutations responsible for FH, providing an accurate diagnosis and leading to early treatment to reduce the risk of premature cardiovascular events.


Hum Mutat


Human mutation


Etxebarria A,Palacios L,Stef M,Tejedor D,Uribe KB,Oleaga A,Irigoyen L,Torres B,Ostolaza H,Martin C




Has Abstract


2012-01-01 00:00:00












  • A new glucose 6 phosphate dehydrogenase variant G6PD Sinnai (34 G-->T). Mutations in brief no. 156. Online.

    abstract::In this paper we report a male infant heterozygous for thalassemia with a mild glucose 6 phosphate dehydrogenase deficiency. The molecular basis of this new Class III G6PD variant is a G-->T mutation at nucleotide 34 in the exon 2, which predicts a Val-->Leu aminoacid substitution at codon 12. We designated this varia...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Galanello R,Loi D,Sollaino C,Dessì S,Cao A,Melis MA

    更新日期:1998-01-01 00:00:00

  • Variants of the ST6GALNAC2 promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy.

    abstract::IgA nephropathy (IgAN) is a polygenic disorder. Increasing evidence has implicated that aberrant glycosylation of IgA1 molecules, including alpha2,6 sialic acid defects, are involved in the pathogenesis of IgAN. In the present study, we designed an association study to investigate polymorphisms of two important genes,...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Li GS,Zhu L,Zhang H,Lv JC,Ding JX,Zhao MH,Shen Y,Wang HY

    更新日期:2007-10-01 00:00:00

  • Homeologous recombination between AluSx-sequences as a cause of hemophilia.

    abstract::Although large deletions from the coagulation factor VIII gene, F8, are responsible for 5% of severe hemophilia A (seHA), few of them have been fully characterised. A detailed description of a large partial deletion of the F8 caused by unequal recombination between homeologous AluSx-derived sequences is presented. The...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Rossetti LC,Goodeve A,Larripa IB,De Brasi CD

    更新日期:2004-11-01 00:00:00

  • Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate.

    abstract::The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investiga...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pezzetti F,Martinelli M,Scapoli L,Carinci F,Palmieri A,Marchesini J,Carinci P,Caramelli E,Rullo R,Gombos F,Tognon M

    更新日期:2004-07-01 00:00:00

  • Whole genome sequencing and mutation rate analysis of trios with paternal dioxin exposure.

    abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or dioxin, is commonly considered the most toxic man-made substance. Dioxin exposure impacts human health and diseases, birth defects and teratogenesis were frequently observed in children of persons who have been exposed to dioxin. However, the impact of dioxin on human muta...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Ton ND,Nakagawa H,Ha NH,Duong NT,Nhung VP,Hien LTT,Hue HTT,Hoang NH,Wong JH,Nakano K,Maejima K,Sasaki-Oku A,Tsunoda T,Fujimoto A,Van Hai N

    更新日期:2018-10-01 00:00:00

  • Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing.

    abstract::Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Klar J,Sobol M,Melberg A,Mäbert K,Ameur A,Johansson AC,Feuk L,Entesarian M,Orlén H,Casar-Borota O,Dahl N

    更新日期:2013-04-01 00:00:00

  • Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked lymphoproliferative disease.

    abstract::Males with an expressed mutation in the SH2D1A gene that encodes an SH2 domain protein named SH2D1A or SAP (NP_002342; signaling lymphocyte activating molecule [SLAM]-associated protein), have an X-linked syndrome characterized by an increased vulnerability to infection with Epstein-Barr virus (EBV). We evaluated two ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Erdõs M,Uzvölgyi E,Nemes Z,Török O,Rákóczi E,Went-Sümegi N,Sümegi J,Maródi L

    更新日期:2005-05-01 00:00:00

  • Microsatellite in the 3' untranslated region of human fibroblast growth factor 9 (FGF9) gene exhibits pleiotropic effect on modulating FGF9 protein expression.

    abstract::Fibroblast growth factor 9 (FGF9) is a member of secreted polypeptide families and involved in many important biological processes, including implantation and morphogenesis during embryogenesis and adult life. Recently, Fgf9-knockout mice exhibited male-to-female sex reversal, demonstrating a novel function for FGF9 i...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Chen TM,Kuo PL,Hsu CH,Tsai SJ,Chen MJ,Lin CW,Sun HS

    更新日期:2007-01-01 00:00:00

  • Array-MLPA: comprehensive detection of deletions and duplications and its application to DMD patients.

    abstract::Multiplex ligation-dependent probe amplification (MLPA) is widely used to screen genes of interest for deletions and duplications. Since MLPA is usually based on size-separation of the amplification products, the maximum number of target sequences that can be screened in parallel is usually limited to approximately 40...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Zeng F,Ren ZR,Huang SZ,Kalf M,Mommersteeg M,Smit M,White S,Jin CL,Xu M,Zhou DW,Yan JB,Chen MJ,van Beuningen R,Huang SZ,den Dunnen J,Zeng YT,Wu Y

    更新日期:2008-01-01 00:00:00

  • Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations.

    abstract::M6P/IGF2R encodes a multifunctional protein involved in lysosomal enzyme trafficking, fetal organogenesis, tumor suppression, and cytotoxic T cell-induced apoptosis. M6P/IGF2R is imprinted and expressed only from the maternally inherited allele in marsupials and rodents. In contrast, humans were initially reported to ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Killian JK,Oka Y,Jang HS,Fu X,Waterland RA,Sohda T,Sakaguchi S,Jirtle RL

    更新日期:2001-01-01 00:00:00

  • Mechanistic insights into the link between a polymorphism of the 3'UTR of the SLC7A1 gene and hypertension.

    abstract::We previously identified the polymorphism ss52051869 in the 3'UTR of human SLC7A1, and demonstrated that it might participate in the apparent link between altered endothelial function, decreased L-arginine and nitric oxide (NO) metabolism, and a genetic predisposition to essential hypertension. Here, we demonstrate th...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Yang Z,Kaye DM

    更新日期:2009-03-01 00:00:00

  • Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders.

    abstract::The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kimberling WJ

    更新日期:2005-11-01 00:00:00

  • HGVS Nomenclature in Practice: An Example from the United Kingdom National External Quality Assessment Scheme.

    abstract::The recommendations for the description of sequence variants from the Human Genome Variation Society (HGVS) were published in 2000. Over the years, the recommendations became widely adopted, especially in human clinical genetics and DNA laboratory reporting. As part of a testing scheme performed by the United Kingdom ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Deans ZC,Fairley JA,den Dunnen JT,Clark C

    更新日期:2016-06-01 00:00:00

  • Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases.

    abstract::Genes and proteins are known to have differences in their sensitivity to alterations. Despite numerous sequencing studies, proportions of harmful and harmless substitutions are not known for proteins and groups of proteins. To address this question, we predicted the outcome for all possible single amino acid substitut...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Schaafsma GCP,Vihinen M

    更新日期:2017-07-01 00:00:00

  • A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.

    abstract::Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with five affected siblings for which no loss-of-function variants were identified by whole exo...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Besse W,Choi J,Ahram D,Mane S,Sanna-Cherchi S,Torres V,Somlo S

    更新日期:2018-03-01 00:00:00

  • Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.

    abstract::Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. I...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Itzkovitz B,Jiralerspong S,Nimmo G,Loscalzo M,Horovitz DD,Snowden A,Moser A,Steinberg S,Braverman N

    更新日期:2012-01-01 00:00:00

  • Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.

    abstract::Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Teich N,Rosendahl J,Tóth M,Mössner J,Sahin-Tóth M

    更新日期:2006-08-01 00:00:00

  • Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.

    abstract::There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementat...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Thompson ER,Boyle SE,Johnson J,Ryland GL,Sawyer S,Choong DY,kConFab,Chenevix-Trench G,Trainer AH,Lindeman GJ,Mitchell G,James PA,Campbell IG

    更新日期:2012-01-01 00:00:00

  • No linkage of P187S polymorphism in NAD(P)H: quinone oxidoreductase (NQO1/DIA4) and type 1 diabetes in the Danish population. DIEGG and DSGD. Danish IDDM Epidemiology and Genetics Group and The Danish Study Group of Diabetes in Childhood.

    abstract::Recent genome screening studies have identified novel regions of possible interest for susceptibility to type 1 diabetes. One of these is a 30-35 cM region mapping to 16q22-q24 (D16S515-D16S520), where also the gene encoding NAD(P)H: quinone oxidoreductase (NQO1) maps. Data has suggested association of a polymorphism ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kristiansen OP,Larsen ZM,Johannesen J,Nerup J,Mandrup-Poulsen T,Pociot F

    更新日期:1999-01-01 00:00:00

  • Detection of heterozygous deletions and duplications in the MECP2 gene in Rett syndrome by Robust Dosage PCR (RD-PCR).

    abstract::Fifty to eighty percent of Rett syndrome (RTT) cases have point mutations in the gene encoding methyl-CpG-binding protein-2 (MECP2). A fraction of MECP2 negative classical RTT patients has large heterozygous deletions. Robust Dosage PCR (RD-PCR) assays were developed as a rapid, convenient and accurate method to detec...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Shi J,Shibayama A,Liu Q,Nguyen VQ,Feng J,Santos M,Temudo T,Maciel P,Sommer SS

    更新日期:2005-05-01 00:00:00

  • wKinMut-2: Identification and Interpretation of Pathogenic Variants in Human Protein Kinases.

    abstract::Most genomic alterations are tolerated while only a minor fraction disrupts molecular function sufficiently to drive disease. Protein kinases play a central biological function and the functional consequences of their variants are abundantly characterized. However, this heterogeneous information is often scattered acr...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Vazquez M,Pons T,Brunak S,Valencia A,Izarzugaza JM

    更新日期:2016-01-01 00:00:00

  • Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion.

    abstract::Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease caused by impaired functioning of human liver aldolase (ALDOB). At least 54 subtle/point mutations and only two large intragenic deletions have been found in the ALDOB gene. Here we report two novel ALDOB variants (p.R46W and p.Y343H) an...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Esposito G,Imperato MR,Ieno L,Sorvillo R,Benigno V,Parenti G,Parini R,Vitagliano L,Zagari A,Salvatore F

    更新日期:2010-12-01 00:00:00

  • Cafe Variome: general-purpose software for making genotype-phenotype data discoverable in restricted or open access contexts.

    abstract::Biomedical data sharing is desirable, but problematic. Data "discovery" approaches-which establish the existence rather than the substance of data-precisely connect data owners with data seekers, and thereby promote data sharing. Cafe Variome ( was therefore designed to provide a general-pur...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lancaster O,Beck T,Atlan D,Swertz M,Thangavelu D,Veal C,Dalgleish R,Brookes AJ

    更新日期:2015-10-01 00:00:00

  • Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines.

    abstract::Recently, we demonstrated that the qualitative American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) guidelines for evaluation of Mendelian disease gene variants are fundamentally compatible with a quantitative Bayesian formulation. Here, we show that the underlying ACMG/AMP "s...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Tavtigian SV,Harrison SM,Boucher KM,Biesecker LG

    更新日期:2020-07-27 00:00:00

  • GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.

    abstract::We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual di...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Au PYB,You J,Caluseriu O,Schwartzentruber J,Majewski J,Bernier FP,Ferguson M,Care for Rare Canada Consortium.,Valle D,Parboosingh JS,Sobreira N,Innes AM,Kline AD

    更新日期:2015-10-01 00:00:00

  • Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications.

    abstract::Galactocerebrosidase (GALC) is a lysosomal beta-galactosidase responsible for the hydrolysis of the galactosyl moiety from several galactolipids, including galactosylceramide and psychosine. The deficiency of this enzyme results in the autosomal recessive disorder called Krabbe disease. It is also called globoid cell ...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Wenger DA,Rafi MA,Luzi P

    更新日期:1997-01-01 00:00:00

  • Screening of thiopurine S-methyltransferase mutations by horizontal conformation-sensitive gel electrophoresis.

    abstract::The genetic polymorphism of thiopurine S-methyltransferase (TPMT) has had a highly significant clinical impact due to its association with individual variation in the toxicity and therapeutic efficiency of thiopurine drugs, which are pharmaceutical agents widely used in the treatment of several kinds of diseases. Unti...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Alves S,Prata MJ,Ferreira F,Amorim A

    更新日期:2000-01-01 00:00:00

  • Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels.

    abstract::This review summarizes the data on 278 different mutations found to date in the genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. A majority (217 mutations; 78% of the total) of the mutations are single-base and either change the codon of a critical amino acid (63%), or lead t...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Kuivaniemi H,Tromp G,Prockop DJ

    更新日期:1997-01-01 00:00:00

  • Databases in the area of pharmacogenetics.

    abstract::In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of crit...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Sim SC,Altman RB,Ingelman-Sundberg M

    更新日期:2011-05-01 00:00:00

  • Harmonized microarray/mutation scanning analysis of TP53 mutations in undissected colorectal tumors.

    abstract::Both the mutational status and the specific mutation of TP53 (p53) have been shown to impact both tumor prognosis and response to therapies. Molecular profiling of solid tumors is confounded by infiltrating wild-type cells, since normal DNA can interfere with detection of mutant sequences. Our objective was to identif...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Favis R,Huang J,Gerry NP,Culliford A,Paty P,Soussi T,Barany F

    更新日期:2004-07-01 00:00:00