Human Molecular Genetics (HUM MOL GENET)

Publisher: Oxford University Press (OUP)

Journal description

Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics neurogenetics chromosome structure and function molecular aspects of cancer genetics gene therapy biochemical genetics major advances in gene mapping understanding of genome organisation In addition the journal also publishes research on other model systems for the analysis of genes especially when there is an obvious relevance to human genetics. Key features of the journal include: Articles - comprehensive reports and definitive research findings of interest to a broad audience of human molecular geneticists. We encourage inclusion of full experimental details with as many display items (figures and tables) as required to tell the complete story. Reports - descriptions of novel results of biological and genetic importance in the field. Commentaries - these discuss recent papers in the journal or review areas of particular interest in the field. Now in its eighth year of publication Human Molecular Genetics has clearly become one of the leading journals in this exciting frontier of scientific research. With the enthusiastic support of the executive editors and editorial board we intend to ensure that the journal's reputation for quality is reinforced in the years to come.

Current impact factor: 6.39

Impact Factor Rankings

2016 Impact Factor Available summer 2017
2014 / 2015 Impact Factor 6.393
2013 Impact Factor 6.677
2012 Impact Factor 7.692
2011 Impact Factor 7.636
2010 Impact Factor 8.058
2009 Impact Factor 7.386
2008 Impact Factor 7.249
2007 Impact Factor 7.806
2006 Impact Factor 8.099
2005 Impact Factor 7.764
2004 Impact Factor 7.801
2003 Impact Factor 8.597
2002 Impact Factor 8.726
2001 Impact Factor 9.318
2000 Impact Factor 9.048
1999 Impact Factor 9.359
1998 Impact Factor 9.307
1997 Impact Factor 8.505
1996 Impact Factor 6.512
1995 Impact Factor 5.273
1994 Impact Factor 4.528
1993 Impact Factor 3.783

Impact factor over time

Impact factor
Year

Additional details

5-year impact 6.85
Cited half-life 6.80
Immediacy index 1.60
Eigenfactor 0.10
Article influence 2.65
Website Human Molecular Genetics website
Other titles Human molecular genetics
ISSN 0964-6906
OCLC 25594670
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

Oxford University Press (OUP)

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Pre-print can only be posted prior to acceptance
    • Pre-print must be accompanied by set statement (see link)
    • Pre-print must not be replaced with post-print, instead a link to published version with amended set statement should be made
    • Pre-print on author's personal website, employer website, free public server or pre-prints in subject area
    • Post-print in Institutional repositories or Central repositories
    • Publisher's version/PDF cannot be used
    • Published source must be acknowledged
    • Must link to publisher version
    • Set phrase to accompany archived copy (see policy)
    • Eligible authors may deposit in OpenDepot
    • The publisher will deposit in PubMed Central on behalf of NIH authors
    • Publisher last contacted on 19/02/2015
    • This policy is an exception to the default policies of 'Oxford University Press (OUP)'
  • Classification
    yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial anomalies have been previously reported in patients' brain and peripheral tissue suggesting their relevance in sporadic Alzheimer's disease. Present work evaluates mitochondrial function and recycling in human fibroblasts and brain biopsies. Functional studies using patients' skin fibroblasts showed slower mitochondrial membrane potential recovery after a mitochondrial insult together with alterations in lysosomes and autophagy, accompanied by an increase of oxidized and ubiquitinated proteins. Impairment in mitophagy has been proven in these cells due to diminished PARK2 and insufficient vesicle induction, accumulating depolarized mitochondria and PINK1. Augmented Δ1 PINK1 fragment levels suggest an inhibitory effect over PARK2 translocation to the mitochondria causing the accumulation of activated PINK1. Moreover, the overexpression of PARK2 diminished ubiquitinated proteins accumulation, improves its targeting to mitochondria and potentiates autophagic vesicle synthesis. This allows the reversion of mitophagy failure reflected in the recovery of membrane potential and the decrease of PINK1 and mitochondria accumulation. Sporadic Alzheimer's disease fibroblasts exhibited similar alterations to what it could be found in patients' hippocampal samples at early stages of the disease, where there was an accumulation of PINK1 and Δ1 PINK1 together with abnormally increased mitochondrial content. Our findings indicate that mitophagy alterations can be considered a new hallmark of sporadic Alzheimer's disease and validates the use of fibroblasts for modelling this pathology.
    No preview · Article · Dec 2015 · Human Molecular Genetics
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    ABSTRACT: Mutations in mitochondrial (mt) genes coding for mt-tRNAs are responsible for a range of syndromes, for which no effective treatment is available. We recently showed that the carboxy-terminal domain (Cterm) of human mt-leucyl tRNA synthetase rescues the pathologic phenotype associated either with the m.3243A>G mutation in mt-tRNALeu(UUR) or with mutations in the mt-tRNAIle, both of which are aminoacylated by Class I mt-aminoacyl-tRNA synthetases (mt-aaRSs). Here we show, by using the human transmitochondrial cybrid model, that the Cterm is also able to improve the phenotype caused by the m.8344A>G mutation in mt-tRNALys, aminoacylated by a Class II aaRS. Importantly, we demonstrate that the same rescuing ability is retained by two Cterm-derived short peptides, β30_31 and β32_33, which are effective towards both the m.8344A>G and the m.3243A>G mutations. Furthermore, we provide in vitro evidence that these peptides bind with high affinity wild-type and mutant human mt-tRNALeu(UUR) and mt-tRNALys, and stabilize mutant mt-tRNALeu(UUR). In conclusion, we demonstrate that small Cterm-derived peptides can be effective tools to rescue cellular defects caused by mutations in a wide range of mt-tRNAs.
    Full-text · Article · Dec 2015 · Human Molecular Genetics
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    ABSTRACT: Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise as a therapeutic tool. The transition to the clinical arena uncovered a number of unforeseen challenges, mainly in the form of a human-specific immune response against the vector that poses a significant limitation in the application of this technology. While the full nature of this response has not been elucidated, long-term expression of therapeutic levels of factor IX is already a reality for a small number of patients. Extending this success to a greater number of hemophilia B patients remains a major goal of the field, as well as translating this strategy to clinical therapy for hemophilia A. This review summarizes the progress of AAV-mediated gene therapy for the hemophilias, along with its upcoming prospects and challenges.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Epilepsy or seizure disorder is among the least understood chronic medical conditions affecting over 65 million people worldwide. Here, we show that disruption of the polycystic kidney disease 2-like 1 (Pkd2l1 or Pkdl), encoding polycystin-L (PCL), a non-selective cation channel, increases neuronal excitability and the susceptibility to pentylenetetrazol-induced seizure in mice. PCL interacts with β2-adrenergic receptor (β2AR) and co-localizes with β2AR on the primary cilia of neurons in the brain. Pkdl deficiency leads to the loss of β2AR on neuronal cilia, which is accompanied with a remarkable reduction in cAMP levels in the central nervous system (CNS). The reduction of cAMP levels is associated with a reduction in the activation of cAMP response element-binding protein, but not the activation of Ca2+/calmodulin-dependent protein kinase II, Akt or mitogen-activated protein kinases. Our data, thus, indicate for the first time that a ciliary protein complex is required for the control of neuronal excitability in the CNS.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Lysosomal storage disorders (LSDs) are a heterogeneous group of inherited diseases with a collective frequency of ∼1 in 7000 births, resulting from the deficiency in one or more enzymes or transporters that normally reside within the lysosomes. Pathology results from the progressive accumulation of uncleaved lipids, glycoproteins and/or glycosaminoglycans in the lysosomes and secondary damages that affect the brain, viscera, bones and connective tissues. Most treatment modalities developed for LSD, including gene therapy (GT), are based on the lysosome-specific cross-correction mechanism, by which close proximity of normal cells leads to the correction of the biochemical consequences of enzymatic deficiency within the neighboring cells. Here, GT efforts addressing these disorders are reviewed with an up-to-date discussion of their impact on the LSD disease phenotype in animal models and patients.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 m ‘1000 Genomes Reference Panel’ imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (PMale = 2 × 10−49, Beta: ∼0.9 SDs per allele), rs8112524 (PMale = 3 × 10−8, Beta: ∼0.25)] and low-frequency variants [rs2385821 (PMale = 6 × 10−31, Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (PHet 0.0003–6.3 × 10−12), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men.
    Full-text · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2308/y male mice. These findings represent a first step toward the validation of an innovative treatment for RTT.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy.
    Full-text · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040CC, which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4+ T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4+ T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4+ T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040CC memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040CC memory CD4+ T cells compared with their rs874040GG counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040CC allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Pallister-Hall Syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations including renal aplasia or hypoplasia, hydroureter, hydronephrosis, or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis, and nephrogenic progenitor self-renewal.
    No preview · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Neuroinflammation, immune reactivity, and mitochondrial abnormalities are considered as causes and/or contributors to neuronal degeneration. Peroxisome proliferator-activated receptors (PPARs) regulate both inflammatory and multiple other pathways that are implicated in neurodegeneration. In the present study, we investigated the efficacy of fenofibrate (Tricor), a pan-PPAR agonist which activates PPAR-alpha as well as other PPARs. We administered fenofibrate to SOD1(G93A) mice daily prior to any detectable phenotypes and then animal behavior, pathology, and longevity were assessed. Treated animals showed significant slowing of the progression of disease with weight loss attenuation, enhanced motor performance, delayed onset and survival extension. Histopathological analysis of the spinal cords showed that neuronal loss was significantly attenuated in fenofibrate treated mice. Mitochondria were preserved as indicated by cytochrome C immunostaining in the spinal cord, which may be partly due to increased expression of the PPAR-gamma coactivator 1-alpha (PGC-1alpha). Total mRNA analysis revealed that neuroprotective and anti-inflammatory genes were elevated, while neuroinflammatory genes were down-regulated. This study demonstrates that activation of PPAR-alpha action via fenofibrate leads to neuroprotection by both reducing neuroinflammation and protecting mitochondria, which leads to a significant increase in survival in SOD1(G93A) mice. Therefore, the development of therapeutic strategies to activate PPAR-alpha as well as other PPARs may lead to new therapeutic agents to slow or halt the progression of ALS.
    No preview · Article · Nov 2015 · Human Molecular Genetics