Several diseases are known which are caused by one or more mutations in linear motifs mediating important interactions. Below you find a selection of such diseases; for linear motifs abused by viruses, see the the dedicated Viruses page. For a large-scale analysis on disease-causing mutations see [Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer? Uyar B, et al., 2014]DISCLAIMER: Some disease descriptions were adapted from the "Online Mendelian Inheritance in Man - An Online Catalog of Human Genes and Genetic Disorders" OMIM.
Noonan-like Syndrome [OMIM:607721]
A S->G mutation at position 2 creates a novel MOD_NMyristoyl site (irreversible modification) resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation [Cordedu et al., 2007].
Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis (FHWHN) [OMIM:248250]
An autosomal recessive wasting disorder of renal Mg2+ and Ca2+ that leads to progressive kidney failure. Here, motifs mediating interaction to PDZ domains are mutated in Claudin 16, abolishing important interactions to the scaffolding protein ZO-1 resulting in lysosomal mislocalization of the protein [Müller et al., 2003, Müller et al., 2006].
Golabi-Ito-Hall Syndrome [OMIM:309500]
IMAGe Syndrome [OMIM:614732]
IMAGE syndrome is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies [Vilain, E. et al. 1999]. The disease locus was mapped to missense mutations in the carboxy terminus of the "Cyclin-dependent kinase inhibitor 1C" protein CDN1C_HUMAN [Arboleda et al. 2012]. This protein plays a key role in the inhibition of cell-cycle progression and is therefore tightly regulated and repressed in most tissues. It contains a CRL4-Cdt2 binding PIP degron annotated at position 270 which is recognized by the CRL4Cdt2 ubiquitin ligase in a PCNA-dependent manner. Mutations in this motif result in excess inhibition of growth and differentiation.
Autosomal Dominant Retinitis Pigmentosa [OMIM:268000]
Under normal circumstances, rhodopsin, associated proteins and lipids are sorted on post-Golgi membranes into a specialized segment of rods, where they perform their important function in signalling upon stimulation with light. Mutations in the C-terminal region of rhodopsin (OPSD_HUMAN, annotated at 344-348) can lead to severe forms of autosomal dominant retinitis pigmentosa in humans by distroying the conserved terminal motif 'QV[SA]PA', resulting in aberrant sub-cellular localisation of rhodopsin [Deretic, 1998]. (For more information about ciliary targeting motifs, see TRG_Cilium_Arf4_1)
β-catenin is a multifunctional protein of the cadherin complex and is an important component of the Wnt signalling pathway. It can act as a cofactor for the TCF/LEF transcription factors and can activate wnt-responsive target genes such as cyclin D1, MMP7, COX2 and others [Lustig et al. 2003]. Mutations in the catenin-gene (CTNNB1) are implicated in various cancers, such as breast cancer [Wang et. al 2008]. Upon phosphorylation by GSK3β at positions S33, S37 and T41 β-catenin binds to E3 ubiquitin ligase β-TrCP via the DEG_SCF_TRCP1_1 phospho-degron (annotated at 32-37) and undergoes proteosomal degradation. Mutations of residue D32, S33 and G34 mediate β-catenin oncogenic activity by preventing degradation and thus stabilizing it [Provost 2005].
Via its role in ectodomain shedding, "Disintegrin and metalloproteinase domain-containing protein 15" Adam15 has been implicated in several diseases, including cancer [Najy AJ, 2008]. Kleino et al. investigated the different alternatively spliced versions of Adam15 and found that different isoforms showed profound differences in interaction partner selection: Exons 18-23 contain different proline-rich regions featuring one or more LIG_SH3_2 binding motifs (annotated at 767-772) and different isoforms bind to specific SH3 domains in different interaction partners: While ADAM15 isoforms i4, i5, and i6 showed a selective ability for strong binding to nephrocystin, ADAM15 i3, containing a unique proline motif not present in other ADAM15 isoforms, bound preferentially to the SH3 domain of Hck tyrosine kinase, whereas the isoform i1, lacking apparent proline-rich clusters, did not bind SH3 domains at all. [Kleino et al., 2009]. The mis-regulation of alternative exon usage of Adam15 can thus significantly influence the protein's interactions and can ultimately lead to cancer [Ortiz et al., 2004].
Burkitt's Lymphoma [OMIM:113970]
The proto-oncogene c-Myc (P01106] is a master-regulator that promotes cell proliferation . The c-Myc protein has a very short half life and is quite unstable because it is rapidly degraded. So, it is found at low copy numbers for a short period of time. Therefore, degradation of c-Myc is an important mechanism for keeping cell proliferating under control . The destruction of c-Myc is accomplished via ubiquitin-mediated proteasomal degradation . The c-Myc protein contains a DEG_SCF_FBW7_1 degron motif at 55 that overlaps the transcription activation domain. Cancer-associated mutations in this degron (Burkitt’s lymphoma (MIM:113970) mutations T58A  and P57S ) impair binding to the E3 ubiquitin ligase, thus leading to defective proteasomal degradation of the c-Myc protein, which causes increased stability and accumulation .
Prostate Cancer [OMIM:176807]
The proto-oncogene ETV1 (UniProt: P50549) is frequently found overexpressed in prostate cancer samples (18563191). The expression level of wild type ETV1 is regulated by the tumor suppressor E3 ubiquitin ligase COP1 (UniProt:Q8NHY2). Binding of COP1 to ETV1 leads to proteasomal degradation of ETV1. However, COP1-mediated proteasomal degradation of ETV1 is impaired because of a translocation event that is recurrently found in prostate cancer samples. The translocation (TMPRSS2:ETV1) encodes a truncated version of ETV1 that is 50-fold more stable than the wild type ETV1 because it does not contain the DEG_COP1 degron motif (Vitari,2011) located at 67-73) in the wild type protein.
X-linked severe congenital neutropenia [OMIM:300299]
Members of the Wiskott-Aldrich syndrome protein WASP family are central hubs in the signaling networks activating the ubiquitous actin-nucleating machine, the Arp2/3 complex [Padrick, 2010]. CDC42 is the most important activator of WASP, binding to its GBD domain (see LIG_GBD_WASP_1) and thus disrupting the auto-inhibition of N-WASP. Devriendt et al. describe a novel disease, X-linked severe congenital neutropenia, which is caused by a novel L270P mutation in the GBD region on WASP [Devriendt 2001]. The mutation abrogates the auto-inhibitory mechanism and constitutively activates the Arp2/3 complex.
The protein aquaporin-0 is a water channel that constitutes more than 60% of the membrane protein content of fibre cells in the ocular lens. Mutations in this protein can cause severely reduced vision caused by clouding of the ocular lens, called cataract. Water permeability of aquaporin-0 is decreased by binding of CaM to the C-terminal cytoplasmic region between residues 225 and 263. Gold et al. showed that "Protein kinase A-anchoring protein 2" AKAP2 binds to aquaporin-0 and thus brings it into proximity with PKA (Protein Kinase A) [Gold, 2011]. In turn, PKA is able to phosphorylate residue S235 [Schey, 1999] of aquaporin-0 which prevents binding of aquaporin-0 to calmodulin (CaM) which subsequently increases water influx through the channel. The (conservative) mutation of an arginine to lysine at position 235 prohibits the phosphorylation of Ser235 and favours CaM binding to sustain the closed conformation of the water channel leading to fibre cell swelling, severe light scattering and early onset of cataracts [Lin, 2007].
Leukemia, acute lymphoblastic; all [OMIM:613065]Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a subtype of acute leukemia, a cancer of the white blood cells. Somatically acquired mutations in several genes have been identified in ALL lymphoblasts, cells in the early stages of differentiation. Germline variation in certain genes may also predispose to susceptibility to ALL (Trevino et al., 2009).
Pilomatrixoma [OMIM:132600]Common benign skin tumor.
Bartter syndrome, antenatal, type 2 [OMIM:241200]An autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. Bartter syndrome type 2 is a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia.
Cherubism [OMIM:118400]An autosomal dominant syndrome characterized by excessive bone degradation of the upper and lower jaws, which often begins around three years of age. It is followed by development of fibrous tissue masses, which causes a characteristic facial swelling.
Familial adenomatous polyposis 1; fap1 [OMIM:175100]Familial adenomatous polyposis-1 is an autosomal dominant disorder characterized by predisposition to cancer. Affected individuals usually develop hundreds to thousands of adenomatous polyps of the colon and rectum, a small proportion of which will progress to colorectal carcinoma if not surgically treated. Gardner syndrome is a variant of FAP in which desmoid tumors, osteomas, and other neoplasms occur together with multiple adenomas of the colon and rectum (Nishisho et al., 1991).
Hemophilia b; hemb [OMIM:306900]Hemophilia B due to factor IX deficiency is phenotypically indistinguishable from hemophilia A (306700), which results from deficiency of coagulation factor VIII (F8; 300841). The classic laboratory findings in hemophilia B include a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT) (Lefkowitz et al., 1993).
Erythrocytosis, familial, 4; ecyt4 [OMIM:611783]Familial erythrocytosis-4 is an autosomal dominant disorder characterized by increased serum red blood cell mass and hemoglobin concentration and elevated serum erythropoietin (EPO; 133170).
Dystonia 6, torsion; dyt6 [OMIM:602629]Dystonia-6 is an autosomal dominant movement disorder characterized by early involvement of craniofacial muscles with secondary generalization often involving the arms, and laryngeal dystonia that causes speech difficulties (review by Djarmati et al., 2009).
Usher syndrome, type ig; ush1g [OMIM:606943]Usher syndrome is an autosomal recessive disorder associated with sensorineural hearing impairment and progressive visual loss attributable to retinitis pigmentosa. The syndrome is both clinically and genetically heterogeneous. Of the 3 different clinical types that have been described, USH1 (276900), consisting of the association of profound congenital deafness, constant vestibular dysfunction, and prepubertal onset retinitis pigmentosa, is the most severe.
Von willebrand disease, type 1; vwd1 [OMIM:193400]Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. The disorder results from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; 300841). F8 is mutated in hemophilia A (review by Goodeve, 2010).
Ovarian cancer [OMIM:167000]Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008).
Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic [OMIM:262190]Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.
Orofacial cleft 11; ofc11 [OMIM:600625]A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum.
Ectodermal dysplasia, anhidrotic, with t-cell immunodeficiency, autosomal [OMIM:612132]A form of ectoderma dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. This form of ectodermal dysplasia is associated with decreased production of pro-inflammatory cytokines and certain interferons, rendering patients susceptible to infection. Mutations in the NFKBIA gene result in functional impairment of NFKB1 (164011), a master transcription factor required for normal activation of immune responses. Interruption of NFKB1 signaling results in decreased production of proinflammatory cytokines and certain interferons, rendering patients susceptible to infection (McDonald et al., 2007).
Colorectal cancer; crc [OMIM:114500]Colorectal cancer is a heterogeneous disease that is common in both men and women. In addition to lifestyle and environmental risk factors, gene defects can contribute to an inherited predisposition to CRC. CRC is caused by changes in different molecular pathogenic pathways, such as chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Chromosome instability is the most common alteration and is present in almost 85% of all cases (review by Schweiger et al., 2013).
Medulloblastoma; mdb [OMIM:155255]Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007).
Hypocalcemia, autosomal dominant 1; hypoc1 [OMIM:601198]Autosomal dominant hypocalcemia-1 is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by Nesbit et al., 2013).
Hypercholesterolemia, familial [OMIM:143890]Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (summary by Hobbs et al., 1992).
Wolfram syndrome 1; wfs1 [OMIM:222300]Wolfram syndrome-1 is a rare and severe autosomal recessive neurodegenerative disease characterized by diabetes mellitus, optic atrophy, diabetes insipidus, and deafness (DIDMOAD). Additional clinical features may include renal abnormalities, ataxia, dementia or mental retardation, and diverse psychiatric illnesses. The minimal diagnostic criteria for Wolfram syndrome are optic atrophy and diabetes mellitus of juvenile onset. Hearing impairment in Wolfram syndrome is typically progressive and mainly affects the higher frequencies, but a small fraction of affected individuals have congenital deafness (summary by Rendtorff et al., 2011).
Liddle syndrome; lidls [OMIM:177200]Liddle syndrome is an autosomal dominant disorder characterized by early-onset salt-sensitive hypertension, hypokalemia, metabolic alkalosis, and suppression of plasma renin activity and aldosterone secretion (summary by Yang et al., 2014).
Gerstmann-straussler disease; gsd [OMIM:137440]Gerstmann-Straussler disease is a rare inherited prion disease characterized by adult onset of memory loss, dementia, ataxia, and pathologic deposition of amyloid-like plaques in the brain (Gerstmann et al., 1936). Gerstmann-Straussler disease typically presents with progressive limb and truncal ataxia, dysarthria, and cognitive decline in the thirties and forties, and the average disease duration is 7 years. GSD can be distinguished from CJD by earlier age at onset, longer disease duration, and prominent cerebellar ataxia (Masters et al., 1981).
Creutzfeldt-jakob disease; cjd [OMIM:123400]The human prion diseases occur in inherited, acquired, and sporadic forms. Approximately 15% are inherited and associated with coding mutations in the PRNP gene. Acquired prion diseases include iatrogenic CJD, kuru (245300), variant CJD (vCJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle. Variant CJD is believed to be acquired from cattle infected with BSE. However, the majority of human cases of prion disease occur as sporadic CJD (sCJD) (Collinge et al., 1996; Parchi et al., 2000; Hill et al., 2003).
Noonan syndrome 5; ns5 [OMIM:611553]The developmental disorder "Noonan Syndrome" can be caused by mutations in Raf-1
which abrogate the interaction with 14-3-3 proteins mediated by corresponding motifs and thereby deregulate the Raf-1 kinase
activity [Pandit et al., 2007].
Insensitivity to pain, congenital, with anhidrosis; cipa [OMIM:256800]Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II.
Stargardt disease 1; stgd1 [OMIM:248200]A common hereditary macular degeneration. It is characterized by decreased central vision, atrophy of the macula and underlying retinal pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina.
Leopard syndrome 2; lprd2 [OMIM:611554]A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
Kabuki syndrome 1; kabuk1 [OMIM:147920]Kabuki syndrome is a congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy (Niikawa et al., 1981).
Noonan-like syndrome [OMIM:607721]A S->G mutation at position 2 creates a novel MOD_NMyristoyl site (irreversible modification) resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation [Cordedu et al., 2007].
Enterohaemorrhagic Escherichia coli
The Wiskott-Aldrich syndrome protein (N-WASP) is an important regulator of the actin cytoskeleton: An intramolecular auto-inhibitory mechanism (LIG_GBD_WASP_1 motif annotated at 467-477 in MEK1), is disrupted by interaction with the Rho-GTPase CDC42, which in turn leads to stimulation the actin-nucleating activity of the Arp2/3 complex. Enterohaemorrhagic Escherichia coli (EHEC) encodes the EspFu protein which is able to mimic the autoinhibitory element within N-WASP and thus activate N-WASP with a potency that is orders of magnitude higher than single endogenous activators [Prehoda, 2000, Sallee, 2008, Padrick, 2010]. By using multiple repeats in one EspFu protein, EHEC is able to interact with multiple N-WASP proteins simultaneously and thus potently stimulate actin polymerization.
The protein "lethal factor" (LEF_BACAN) is a metalloprotease that specifically targets MKKs (mitogen-activated protein kinase kinases) MEK1, MEK2, MKK3, MKK4, MKK6, and MKK7. These kinases are important regulators of signal transduction as they phosphorylate and thus activate specific MAPKs (such as ERK1, ERK2, p38 or JNK). Bacillus anthracis' "lethal factor" cleaves its MKK substrates within or close to the MAPK docking sites (eg. annotated at 3-11 in MEK1), thus effectively preventing the MKK to dock to its MAPK [Bardwell, 2004].
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement