Functional analysis and classification of homozygous and hypomorphic ABCA4 variants associated with Stargardt macular degeneration.


:Stargardt macular degeneration (Stargardt disease 1 [STGD1]) is caused by mutations in the gene encoding ABCA4, an ATP-binding cassette protein that transports N-retinylidene-phosphatidylethanolamine (N-Ret-PE) across photoreceptor membranes. Reduced ABCA4 activity results in retinoid accumulation leading to photoreceptor degeneration. The disease onset and severity vary from severe loss in visual acuity in the first decade to mild visual impairment late in life. We determined the effect of 22 disease-causing missense mutations on the expression and ATPase activity of ABCA4 in the absence and presence of N-Ret-PE. Three classes were identified that correlated with the disease onset in homozygous STGD1 individuals: Class 1 exhibited reduced ABCA4 expression and ATPase activity that was not stimulated by N-Ret-PE; individuals homozygous for these variants had an early disease onset (≤13 years); Class 2 showed reduced ATPase activity with limited stimulation by N-Ret-PE; these correlated with moderate disease onset (14-40 years); and Class 3 displayed high expression and ATPase activity that was strongly activated by N-Ret-PE; these were associated with late disease onset (>40 years). On the basis of our results, we introduce a functionality index for gauging the effect of missense mutations on STGD1 severity. Our studies support the mild phenotype exhibited by the p.Gly863Ala, p.Asn1868Ile, and p.Gly863Ala/p.Asn1868Ile variants.


Hum Mutat


Human mutation


Curtis SB,Molday LL,Garces FA,Molday RS




Has Abstract


2020-11-01 00:00:00












  • Effects of a 9.6-kb deletion of the LDL receptor gene (FH Helsinki) on structure and levels of mRNA.

    abstract::FH Helsinki is a deletion of the low-density lipoprotein receptor (LDLR) gene that deletes 9.6 kb from intron 15 to exon 18. Screening for mutant transcripts by Northern blot analysis from a patient heterozygous for FH Helsinki revealed two mutant transcripts. One was a transcript where the proximal part of intron 15 ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Rødningen OK,Tonstad S,Ose L,Berg K,Leren TP

    更新日期:1998-01-01 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

  • Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia.

    abstract::Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic α'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Weisschuh N,Stingl K,Audo I,Biskup S,Bocquet B,Branham K,Burstedt MS,De Baere E,De Vries MJ,Golovleva I,Green A,Heckenlively J,Leroy BP,Meunier I,Traboulsi E,Wissinger B,Kohl S

    更新日期:2018-10-01 00:00:00

  • Common variation in GRB-associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia.

    abstract::GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE epsilon4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belg...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sleegers K,Bettens K,Brouwers N,Engelborghs S,van Miegroet H,De Deyn PP,Van Broeckhoven C

    更新日期:2009-02-01 00:00:00

  • Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency.

    abstract::During the last 10 years, an increasing number of genes have been identified whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3-gene, encoding for a tyrosine kinase that is functionally coupled to cytokine receptors which...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Notarangelo LD,Mella P,Jones A,de Saint Basile G,Savoldi G,Cranston T,Vihinen M,Schumacher RF

    更新日期:2001-10-01 00:00:00

  • mirVAFC: A Web Server for Prioritizations of Pathogenic Sequence Variants from Exome Sequencing Data via Classifications.

    abstract::Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Li Z,Liu Z,Jiang Y,Chen D,Ran X,Sun ZS,Wu J

    更新日期:2017-01-01 00:00:00

  • Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.

    abstract::Mutations underlying FH in Spain are largely unknown because only a few and limited surveys have been carried out on Spanish FH patients up to now. To gain information on this issue, we have analysed a group of 113 unrelated Spanish FH patients from an eastern area of Spain (Valencian Community). We have screened the ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: García-García AB,Real JT,Puig O,Cebolla E,Marín-García P,Martínez Ferrandis JI,García-Sogo M,Civera M,Ascaso JF,Carmena R,Armengod ME,Chaves FJ

    更新日期:2001-11-01 00:00:00

  • Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine.

    abstract::Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome-based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the gene...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Jarjanazi H,Kiefer J,Savas S,Briollais L,Tuzmen S,Pabalan N,Ibrahim-Zada I,Mousses S,Ozcelik H

    更新日期:2008-04-01 00:00:00

  • Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene.

    abstract::Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene at Xq22.1. Studies of the mutations in unrelated Fabry families have identified a variety of lesions indicating the molecular genetic heterogeneity underlying the disease. Forty-nine differ...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Eng CM,Desnick RJ

    更新日期:1994-01-01 00:00:00

  • VAR-MD: a tool to analyze whole exome-genome variants in small human pedigrees with mendelian inheritance.

    abstract::The analysis of variants generated by exome sequencing (ES) of families with rare Mendelian diseases is a time-consuming, manual process that represents one barrier to applying the technology routinely. To address this issue, we have developed a software tool, VAR-MD (, f...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sincan M,Simeonov DR,Adams D,Markello TC,Pierson TM,Toro C,Gahl WA,Boerkoel CF

    更新日期:2012-04-01 00:00:00

  • Tissue distribution of the ND4/11778 mutation in heteroplasmic lineages with Leber hereditary optic neuropathy.

    abstract::Leber hereditary optic neuropathy (LHON) is a maternally inherited eye disease most commonly caused by mitochondrial DNA (mtDNA) point mutation at position 11778, 3460, or 14484. Approximately 14% of families show heteroplasmy for the pathogenic mutations but little is known about the mutational burden in different ti...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Juvonen V,Nikoskelainen E,Lamminen T,Penttinen M,Aula P,Savontaus ML

    更新日期:1997-01-01 00:00:00

  • Homocystinuria in the Arab population of Israel: identification of two novel mutations using DGGE analysis.

    abstract::This study describes, for the first time, a thorough genetic investigation in Israeli Arab homocystinuric patients. By using a DGGE methodology and sequencing we were able to identify the disease causing mutation in all. Of the mutations that were detected, two are novel: a 785C>G transversion in exon 7 (T262R) and a ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Gat-Yablonski G,Mandel H,Fowler B,Taleb O,Sela BA

    更新日期:2000-10-01 00:00:00

  • Somatic expansion in mouse and human carriers of fragile X premutation alleles.

    abstract::Repeat expansion diseases result from expansion of a specific tandem repeat. The three fragile X-related disorders (FXDs) arise from germline expansions of a CGG•CCG repeat tract in the 5' UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. We show here that in addition to germline expansion, ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lokanga RA,Entezam A,Kumari D,Yudkin D,Qin M,Smith CB,Usdin K

    更新日期:2013-01-01 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

  • Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients.

    abstract::Classical citrullinemia (CTLN1), a rare autosomal recessive disorder, is caused by mutations of the argininosuccinate synthetase (ASS) gene, localized on chromosome 9q34.1. ASS functions as a rate-limiting enzyme in the urea cycle. Previously, we identified 32 mutations in the ASS gene of CTLN1 patients mainly in Japa...

    journal_title:Human mutation

    pub_type: 杂志文章,多中心研究


    authors: Gao HZ,Kobayashi K,Tabata A,Tsuge H,Iijima M,Yasuda T,Kalkanoglu HS,Dursun A,Tokatli A,Coskun T,Trefz FK,Skladal D,Mandel H,Seidel J,Kodama S,Shirane S,Ichida T,Makino S,Yoshino M,Kang JH,Mizuguchi M,Barshop BA

    更新日期:2003-07-01 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

  • Autosomal-dominant early-onset spastic paraparesis with brain calcification due to IFIH1 gain-of-function.

    abstract::We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or de...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Ruaud L,Rice GI,Cabrol C,Piard J,Rodero M,van Eyk L,Boucher-Brischoux E,de Noordhout AM,Maré R,Scalais E,Pauly F,Debray FG,Dobyns W,Uggenti C,Park JW,Hur S,Livingston JH,Crow YJ,Van Maldergem L

    更新日期:2018-08-01 00:00:00

  • A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype.

    abstract::Oculodentodigital dysplasia (ODDD) and Hallermann-Streiff syndrome (HSS) share several clinical characteristics. However, while ODDD is a dominantly inherited disorder due to mutations in the connexin 43 gene GJA1, the inheritance pattern of the HSS syndrome is still debated. Overlapping phenotypes have been described...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pizzuti A,Flex E,Mingarelli R,Salpietro C,Zelante L,Dallapiccola B

    更新日期:2004-03-01 00:00:00

  • DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype.

    abstract::Antisense oligonucleotide (AON)-mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Wang RT,Barthelemy F,Martin AS,Douine ED,Eskin A,Lucas A,Lavigne J,Peay H,Khanlou N,Sweeney L,Cantor RM,Miceli MC,Nelson SF

    更新日期:2018-09-01 00:00:00

  • Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.

    abstract::Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskele...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Böhm J,Biancalana V,Dechene ET,Bitoun M,Pierson CR,Schaefer E,Karasoy H,Dempsey MA,Klein F,Dondaine N,Kretz C,Haumesser N,Poirson C,Toussaint A,Greenleaf RS,Barger MA,Mahoney LJ,Kang PB,Zanoteli E,Vissing J,Wittin

    更新日期:2012-06-01 00:00:00

  • Next-generation genetic testing for retinitis pigmentosa.

    abstract::Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retina...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Neveling K,Collin RW,Gilissen C,van Huet RA,Visser L,Kwint MP,Gijsen SJ,Zonneveld MN,Wieskamp N,de Ligt J,Siemiatkowska AM,Hoefsloot LH,Buckley MF,Kellner U,Branham KE,den Hollander AI,Hoischen A,Hoyng C,Klevering BJ

    更新日期:2012-06-01 00:00:00

  • A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity.

    abstract::Recessively inherited limb girdle muscular dystrophy (LGMD) type 2A is the most common LGMD worldwide. Here, we report the first single missense variant in CAPN3 causing dominantly inherited calpainopathy. A 43-year-old proband, his father and two sons were heterozygous for a c.1715G>C p.(Arg572Pro) variant in CAPN3. ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Vissing J,Dahlqvist JR,Roudaut C,Poupiot J,Richard I,Duno M,Krag T

    更新日期:2020-09-01 00:00:00

  • Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus.

    abstract::Alpha-chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of au...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Rad A,Schade-Mann T,Gamerdinger P,Yanus GA,Schulte B,Müller M,Imyanitov EN,Biskup S,Löwenheim H,Tropitzsch A,Vona B

    更新日期:2020-11-10 00:00:00

  • Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients.

    abstract::The entire NF1 coding region was analyzed for mutations in a panel of 108 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 10 mutations which have never been reported before. Clinical diagnosis of NF1 was established according to the NIH consensus criteria in 100 individuals, while 8 were ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Origone P,De Luca A,Bellini C,Buccino A,Mingarelli R,Costabel S,La Rosa C,Garrè C,Coviello DA,Ajmar F,Dallapiccola B,Bonioli E

    更新日期:2002-07-01 00:00:00

  • Molecular basis of recessive congenital methemoglobinemia, types I and II: Exon skipping and three novel missense mutations in the NADH-cytochrome b5 reductase (diaphorase 1) gene.

    abstract::Hereditary methemoglobinemia due to reduced nicotin amide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5r) deficiency is classified into an erythrocyte type (I) and a generalized type (II). We investigated the b5r gene of three unrelated patients with types I and II and found four novel mutations. The patient...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kugler W,Pekrun A,Laspe P,Erdlenbruch B,Lakomek M

    更新日期:2001-04-01 00:00:00

  • Identification of novel polymorphisms in the pM5 and MRP1 (ABCC1) genes at locus 16p13.1 and exclusion of both genes as responsible for pseudoxanthoma elasticum.

    abstract::Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connective tissue, characterized by progressive calcification of the elastic fibers in the eye, the skin, and the cardiovascular system. The PXE locus has been mapped to chromosome 16p13.1, and was recently further refined to a 500 kb-region, containi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Perdu J,Germain DP

    更新日期:2001-01-01 00:00:00

  • Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides.

    abstract::Cystic fibrosis (CF), the most common life-threatening genetic disease in Caucasians, is caused by ∼2,000 different mutations in the CF transmembrane conductance regulator (CFTR) gene. A significant fraction of these (∼13%) affect pre-mRNA splicing for which novel therapies have been somewhat neglected. We have previo...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Igreja S,Clarke LA,Botelho HM,Marques L,Amaral MD

    更新日期:2016-02-01 00:00:00

  • Cytogenetically visible inversions are formed by multiple molecular mechanisms.

    abstract::Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short-read whole-gen...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pettersson M,Grochowski CM,Wincent J,Eisfeldt J,Breman AM,Cheung SW,Krepischi ACV,Rosenberg C,Lupski JR,Ottosson J,Lovmar L,Gacic J,Lundberg ES,Nilsson D,Carvalho CMB,Lindstrand A

    更新日期:2020-11-01 00:00:00

  • Mutational analysis of the HGSNAT gene in Italian patients with mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Mutation in brief #959. Online.

    abstract::Mucopolysaccharidosis (MPS) describes any inherited lysosomal storage disorder resulting from an inability to catabolize glycosaminoglycans. MPS III (or Sanfilippo syndrome) is an autosomal recessive disease caused by a failure to degrade heparan sulphate. There are four subtypes of MPS III, each categorized by a defi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Fedele AO,Filocamo M,Di Rocco M,Sersale G,Lübke T,di Natale P,Cosma MP,Ballabio A

    更新日期:2007-05-01 00:00:00

  • Spectrum of GJB2 mutations in Turkey comprises both Caucasian and Oriental variants: roles of parental consanguinity and assortative mating.

    abstract::Considerable differences exist for the spectrum of GJB2 mutations in different populations. Screening for the c.35delG mutation in 256 independent probands, 154 multiplex (familial) and 102 simplex (sporadic), coming from different regions of Turkey revealed 37 (14.5%) homozygotes. The allele frequency of c.35delG ran...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Tekin M,Duman T,Boğoçlu G,Incesulu A,Comak E,Ilhan I,Akar N

    更新日期:2003-05-01 00:00:00