Human Mutation

Cover image for Vol. 35 Issue 5

Edited By: Richard G.H. Cotton and Garry R. Cutting

Impact Factor: 5.213

ISI Journal Citation Reports © Ranking: 2012: 22/161 (Genetics & Heredity)

Online ISSN: 1098-1004

Featured

  • Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues

    Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues

    Activating mutations of protein kinases play a key role in tumorogenesis and are targets for new generations of drugs. We performed the first analysis of the 407 activating mutations described in the literature, with affect 41 protein kinases. Activating mutations do not associate with conserved or catalytic residues but cluster around three segments that act as “brakes” of the kinase activity (HS1–HS3). Therefore, bioinformatics methods based on conservation can not be used to predict activating mutations and new tools are needed.

  • Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains

    Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains

    In this study, we identified the same duplication of 500 kb on the X chromosome in unrelated male patients with intellectual disability. From the different genes included, the RAB39B gene was our prime candidate because loss-of-function had been described in relation to this condition. Indeed, overexpression of this gene in primary neuronal cells resulted in a decrease of neuronal branching and presynaptic terminals, providing evidence that an increased dosage of RAB39B in humans can affect neuronal development and function.

  • Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality

    Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality

    Loss-of-function mutations in the PIGA gene are normally lethal in utero. In this study however, we report a loss-of-function PIGA mutation in boys from a large family who were diagnosed with a severe form of intellectual disability. Based on functional assays, we provide evidence that this mutation results in the production of a shorter PIGA protein with residual functionality which is sufficient to rescue the lethality but still results in clinical features including intellectual disability.

  • Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies

    Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies

    We characterize fibroblasts from muscular dystrophy patients with mutations in the nuclear proteins emerin and LAP2alpha in combination with SUN1 mutations and identify changes in cell size, proliferation, centrosome positioning, senescence and cell migration. At the biochemical level the SUN1 mutations affect the interaction with lamin A/C and emerin. This affects the tested cellular properties. We conclude that the presence of two faulty nuclear genes associated with maintaining nuclear envelope structure and function produces both a more severe cellular and clinical phenotype.

  • Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)

    Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)

    The lysosomal disorder mucolipidosis II (MLII) is caused by mutations in GNPTAB encoding an α/β-subunit precursor protein of the oligomeric Golgi-resident GlcNAc-1-phosphotransferase. This enzyme forms mannose 6-phosphate targeting signals on lysosomal enzymes prerequisite for lysosomal function. Here, we analyzed the expression of six missense and frameshift mutations identified in patients and found that they either affect ER-Golgi transport, site-1 protease mediated proteolytic activation or mRNA stability of the α/β-subunit precursor protein, and associate with different clinical courses of the disease

  • Activating Mutations Cluster in the “Molecular Brake” Regions of Protein Kinases and Do Not Associate with Conserved or Catalytic Residues
  • Increased Dosage of RAB39B Affects Neuronal Development and Could Explain the Cognitive Impairment in Male Patients with Distal Xq28 Copy Number Gains
  • Early Frameshift Mutation in PIGA Identified in a Large XLID Family Without Neonatal Lethality
  • Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies
  • Mucolipidosis II-Related Mutations Inhibit the Exit from the Endoplasmic Reticulum and Proteolytic Cleavage of GlcNAc-1-Phosphotransferase Precursor Protein (GNPTAB)

Recently Published Issues

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New Video Highlight

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New video highlight created by Maria Chiara Scaini on her recently published Human Mutation paper entitled, "CDKN2A Unclassified Variants in Familial Malignant Melanoma: Combining Functional and Computational Approaches for Their Assessment."

Conferences

16th International Workshop on TP53

16th International Workshop on TP53




Golden Helix Summer Schools

Pharmacogenomics and Genomic Medicine
Apollo Resort hotel
Aegina island, GREECE
Sep 11-15, 2014

New Virtual Issue

Please see the new Virtual Issue, "Recommendations and Standards for the Reporting and Databasing of Genetic Variations", guest edited by Johan den Dunnen and Mauno Vihinen. Articles in this Virtual Issue have been made freely available online.

See also this valuable Virtual Issue on assessing pathogenicity of gene variants – also free online

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