Table I.
Human Diseases and Associated Membrane Trafficking Defects
| Human disease | Protein | Membrane trafficking defect | Clinical features | References | OMIMa |
|---|---|---|---|---|---|
| α1‐Antitrypsin deficiency | α1‐Antitrypsin | Inhibited export from the ER of this secreted protein. Lung and liver damage by proteases | Emphysema and liver cirrhosis | (Perlmutter, 2004) | 107400 |
| Acute myeloid leukemia | Endophillin II | Clathrin–coated pit formation | Leukemia | (Dreyling 1996, Jones 2001, Narita 1999, Tebar 1999) | 604465 |
| Alzheimer's disease | Presenilin 1 | Presenilin 1–involved in cleavage and trafficking of amyloid precursor protein to plasma membrane | Neurodegenerative disorder | (Uemura et al., 2004) | 104300 |
| Tau | Tau – microtubular stability through formation of aggregates | ||||
| Autosomal dominant polycystic kidney disease (ADPKD) | Polycystin‐1 or 2 | Causes a defect in E‐cadherin assembly and basolateral trafficking | Renal cysts in kidney and other tissues leading to end‐ stage renal failure | (Charron et al., 2000) | 173900 |
| Autosomal dominant retinitis pigmentosa | Rhodopsin | Inhibited interaction of rhodopsin and ARF4, leading to inhibited post‐Golgi delivery to rod outer segment | Narrowing of visual fields, night blindness | (Deretic et al., 2005) | 180380 |
| Autosomal dominant ventricular tachycardia | Ryanodine receptor | Mutations in lumenal and transmembrane domains | Cardiac arrhythmia, hyperthermia | (Yano et al., 2005) | 604722 |
| Autosomal recessive primary hyperoxaluria | Alanine‐glyoxylate aminotransferase | Mistargeting of peroxisomal proteins to mitochondria | Kidney disease | (Danpure, 1998) | 259900 |
| Aβ‐lipoproteinaemia | MTP | ER retention thus preventing ApoB secretion | Vascular disease | (Sharp et al., 1993) | 200100 |
| Batten's disease | CLN1‐CLN8 | Group of gene products implicated in regulating the processing and targeting of lysosomal and synaptic proteins | Neurological disease | (Pearce, 2000) | 204200 |
| Breast cancer | Caveolin‐1 | Deletion or dominant negative mutation of caveolin‐1 promotes tumor progression | Breast cancer | (Bouras et al., 2004; Williams and Lisanti, 2005) | 601047 |
| Brugada syndrome | SCN5A, α subunit of cardiac sodium channel | ER retention of sodium channel subunits and defective cell surface sodium transport | Cardiac disease | (Baroudi et al., 2004) | 601144 |
| Charcot‐Marie‐Tooth disease, demyelinating, type 1B | Myelin protein zero gene, MPZ | ER retention of integral membrane protein | Neurological and degenerative muscle disease | (Hayasaka 1993, Matsuyama 2002) | 118200 |
| Charcot‐Marie‐Tooth disease, axonal, type 2A1 | KIF1B | Microtubular transport of synaptic vesicles | Neurological and degenerative muscle disease | (Zhao et al., 2001) | 118210 |
| Chediak‐Higashi syndrome (CHS) | CHS1/Lyst | Lyst involved in regulation of protein secretion from lysosomes – enlarged lysosomes | Partial albinism, recurrent bacterial infections, impaired chemotaxis and abnormal natural killer cell function | (Shiflett 2002, Ward 2003) | 214500 |
| Choroideremia (CHM) | Rab Escort Protein 1 (REP1) | RAB27a remains cytosolic due to defective geranylgeranyl modification in CHM lymphoblasts | X‐linked form of retinal degeneration | (Seabra et al., 2002) | 303100 |
| Combined factors V and VIII deficiency | ERGIC‐53/p58 C‐type lectin | ER retention and defective secretion of factors V and VIII | Blood disease | (Nichols et al., 1998) | 227300 |
| Congenital Finnish nephritic syndrome | Nephrin (NPHS1), podocin (NPHS2) | ER retention | Kidney inflammation | (Kestila 1998, Kramer‐Zucker 2005) | 256300 600995 |
| Congenital hyperinsulinism | Pancreatic ATP‐sensitive potassium channel (K‐ATP) | ER or Golgi retention of K‐ATP due to mutations in its sulfonylurea‐1 (SUR1) subunit | Excess insulin leading to hypoglycaemia | (Dunne 2004, Yan 2004) | 602485 |
| Congenital hypothyroid goiter | Thyroglobulin | ER storage disease. Thyroglobulin is misfolded and accumulates in ER | Constipation, large tongue, swelling around the eyes, failure to suckle, mental retardation | (Hishinuma 1998, Kim 1998) | 188450 |
| Congenital sucrase‐isomaltase deficiency | Sucrase‐isomaltase | ER retention instead of brush border membrane localization | Gastrointestinal disease | (Naim et al., 1998) | 222900 |
| Cystic fibrosis | Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel | Trafficking of the chloride channel to the plasma membrane is defective | Multi‐organ disease, most commonly lungs and pancreas | (Heda et al., 2001) | 219700 |
| Demyelinating polyneuropathy | EEA1 | Autoantibody against EEA1 | Limb weakness | (Selak et al., 2003) | 605070 |
| Dent's disease | CLC‐5 voltage‐gated chloride channel | Inhibited post‐Golgi transport to cell surface | Progressive renal failure | (Carr 2003, Ludwig 2005) | 300009 |
| Diabetes insipidus (nephrogenic) | Vasopressin V2 receptor | ER storage disease leading to retention of receptor in the ER | Excessive water secretion through kidneys (diabetes insipidus) | (Kim 1998, Morello 2000) | 304800 |
| Diabetes mellitus (Type 2) | Insulin receptor | Functional defects or ER retention | Diabetes mellitus; polyuria, polydipsia, tiredness, increased appetite | (Kadowaki et al., 1991) | 125853 |
| Dubin‐Johnson syndrome | MRP2 | ER retention | Liver disease | (Mor‐Cohen et al., 2001) | 237500 |
| Fabry's disease | α‐Galactosidase A | In this fat storage disorder, lysosomal α‐galactosidase is retained in the ER, preventing degradation of glycosphingolipids | Cloudiness of eyes, burning sensation in hands and feet, skin blemishes, renal failure, myocardial infarction | (Fan 1999, Garman 2002) | 301500 |
| Familial hemophagocytic lymphoschistiocytosis (FHL) | Perforin | Perforin – defective CTL (cytotoxic T lymphocytes) mediated killing | Immunodeficiency | (Feldmann 2003, Stepp 1999) | 603553 |
| Munc 13–4 | Munc 13–4 – inhibited release of secretory lysosomes from CTLs | ||||
| Familial hypercholesterolemia | Low density lipoprotein receptor (LDLR) | ER retention and degradation of LDLR | Increased blood cholesterol, atherosclerosis, heart disease | (Defesche, 2004) | 143890 |
| Familial intrahepatic cholestasis | MDR3 | ABC transporter of phosphatidylcholine out of cell | Liver disease | (de Vree et al., 1998) | 602347 |
| Griscelli syndrome | Myosin Va or Rab27A | Inhibited transport of melanosomes to plasma membrane in melanocytes | Albinism, silvery hair, neurological defects, immunodeficiency | (Menasche et al., 2000) | 214450 607624 |
| Hereditary myeloperoxidase | MPO | ER retention and degradation | Cancer, immunodeficiency | (DeLeo et al., 1998) | 606989 |
| Hereditary hemochromatosis | Hemochromatosis (HFE) | Mutant HFE fails to bind transferrin receptor at cell surface, resulting in iron overload | Liver cirrhosis, diabetes mellitus, cardiomyopathy | (Miyajima, 2002) | 235200 |
| Hereditary spherocytosis | Chloride/bicarbonate anion exchanger | Misfolding and accumulation in the ER without rapid degradation or severe aggregation | Blood disease | (Quilty and Reithmeier, 2000) | 182900 |
| Hermansky‐Pudlak syndrome | β subunit of AP3 | AP3 – compromised lysosomal trafficking | Partial albinism, bleeding, ceroid accumulates in lysosomal structures | (Detter 2000, Huizing 2002) | 203300 |
| RabGGT‐α subunit | RabGGT‐α – inhibited Rab prenylation and membrane association | ||||
| Human neutropenia | Neutrophil elastase Occasionally other genes | Cyclic neutropenia. Excessive routing of NE to granules | Alternate 21 day cycling of neutrophils and monocytes | (Benson 2003, Berliner 2004, Horwitz 2004) | 162800 |
| Severe congenital neutropenia. Impaired association with AP3; NE redirected from lysosome to plasma membrane | Promyelocytic arrest in bone marrow | 202700 | |||
| Huntington's disease | Huntingtin (htt) | Microtubular transport of BDNF | Neurodegeneration | (Gauthier et al., 2004) | 143100 |
| I‐cell disease | NAGT1 phosphotransferase | Defect in mannose‐6‐ phosphate addition to lysosomal enzymes resulting in aberrant targeting | Neurological disease | (Ben‐Yoseph et al., 1987) | 252500 |
| Laron syndrome | Growth hormone receptor | Low levels of cell surface protein caused by ER retention | Dwarfism | (Wojcik et al., 1998) | 245590 |
| Leukocyte adhesion deficiency type I | CD18 | Leukocyte rolling and adhesion during immune reaction | Recurrent bacterial and fungal infections, poor wound healing | (Hogg 1999, Mathew 2000) | 116920 |
| Limb girdle muscular dystrophy 1C, rippling muscle disease, distal myopathy | Caveolin‐3 | Abnormal caveolin‐3 traps normal caveolin‐3 in the Golgi of skeletal muscle cells | Muscle diseases | (Woodman et al., 2004) | 601253 |
| Lissencephaly | LIS1 or doublecortin | Microtubular motor function or stabilization of microtubules | Retardation, epilepsy | (Reiner et al., 1993) | 607432 |
| Listeria monocytogenes infection | Hepatocyte growth factor receptor (HGFR) | HGFR on the host cell internalizes bacteria via binding to the surface protein internalin B | Symptoms of food poisoning | (Li, et al., 2005b) | 164860 |
| Long QT‐2 syndrome | Human ether‐a‐go‐go (HERG) potassium channel | ER retention of HERG preventing trafficking to cell surface | Abnormal electrical cardiac impulses and ventricular tachycardia | (Kupershmidt et al., 2002) | 192500 |
| Menkes' disease | ATP7A (Menkes disease protein) | Mislocalization and/or degradation of this copper transporter leads to copper deficiency | Mental retardation, skeletal abnormalities, kinky hair. Usually lethal before the age of 3 | (Lutsenko and Petris, 2003) | 309400 |
| Multiple exostoses syndrome | Golgi‐localized EXT1 and EXT2 complex | Mutations reducing glucoronyltransferase and N‐acetyl‐D‐ glucosaminotransferase activity inhibit post‐ER transport of EXT1/EXT2 | Skeletal dysplasia, connective tissue disorder | (McCormick et al., 2000) | 133700 |
| Nephrogenic diabetes insipidus | Water channel aquaporin‐2 | ER retention; some AQP2 mutants can leave ER using chemical chaperones | Excessive water secretion through kidneys (dilute urine and excess water loss) | (Tamarappoo et al., 1999) | 125800 |
| Niemann‐Pick disease type C | NPC1 | Lysosomal accumulation of LDL‐derived cholesterol | Neurodegenerative disease | (Liscum, 2000) | 257220 |
| Occipital horn syndrome | ATP7A (Menkes disease protein) | ER retention of ATP7A results in a milder form of Menkes disease | Mental retardation, skeletal abnormalities | (Kaler 1998, Qi 1998) | 304150 |
| Ocular and oculocutaneous albinism | Tyrosinase, GPCR‐like OA1 gene product | Unstable or mislocalized proteins | Eye pigmentation defects | (D'Addio et al., 2000) | 300500 |
| Oculocerebrorenal syndrome of Lowe | OCRL1 | Perturbed endosome‐to‐ TGN trafficking | Cataracts, mental retardation, renal failure | (Lowe, 2005) | 309000 |
| Osteogenesis imperfecta | Type I collagen | Defective trafficking or ER retention of collagen | Brittle bones and teeth, hearing loss | (Pochampally et al., 2005) | 166200 |
| Paraneoplastic stiff‐person syndrome | Amphiphysin I | Clathrin‐coated vesicle formation compromised | Autoimmune disease | (De Camilli et al., 1993) | 184850 |
| Pelizaeus‐Merzbacher disease | Proteolipid protein (PLP) gene | ER retention leading to ER stress signaling and apoptosis | Neurological disease | (Gow et al., 1998) | 312080 |
| Pendred syndrome | Pendrin (anion transporter) | ER retention of a cell surface iodide transporter | Hypothyroidism, deafness | (Taylor et al., 2002) | 274600 |
| Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) | Potassium channel (Kir6.2) and sulfonylurea receptor (SUR1) subunits | ER or TGN retention of a cell surface potassium channel involved in insulin secretion | Hyperinsulinism, hypoglycemia | (Taschenberger et al., 2002) | 601820 |
| Prion diseases | Prion protein (PrP) | Abnormal PrP accumulate in the ER; perturbed trafficking to cell surface | Neurodegenerative disorders | (Harris, 2003) | 176640 |
| Rhizomelic chondrodysplasia puncta | Pex7 | Defective import of peroxisomal matrix proteins | Skeletal defect, neurological disease | (Terlecky and Fransen, 2000) | 215100 |
| Stargardt‐like macular dystrophy | ABCA4 gene; vitamin A transport | Defective localization | Blindness | (Edwards 2001, Sun 1999) | 248200 |
| Usher's syndrome | Myosin VIIA | Melanosome transport | Blindness, deafness | (Liu et al., 1998) | 276903 |
| Wilson's disease | ATP7B (Wilson's disease protein) | ER retention and inhibited secretion of copper‐containing enzymes from liver | Neurological disease, liver cirrhosis | (Cox and Gitlin, 2003; Moore, 2002) | 277900 |
| Wiskott‐Aldrich syndrome | Wiskott‐Aldrich syndrome protein (WASP) | WASP regulation of actin cytoskeleton | Immunodeficiency, autoimmune disease, hematologic malignancy | (Burns et al., 2004) | 301000 |
a
Online Mendelian Inheritance in Man reference at http://www.ncbi.nlm.nih.gov/omim/.