HomeFunctional AnalysisLinking human disease genes and C. elegans genes

Although the phenotypes of the human diseases and the mutant defects in C. elegans seem about as unrelated as possible, the cellular and molecular details of many of these defects are highly related. Using C. elegans as a model organism, much can be learned at the cellular and molecular level about a specific biological process, by understanding the mode of action of the orthologous genes involved.

The recent findings suggest the absence of the mammalian organ(s) affected by a disease does not preclude the use of nematodes to shed light on complex disease mechanisms and find novel target genes for treatments. For example, the ksr gene, discovered in C. elegans has recently been proposed as a druggable target to overcome Ras-driven cancers (1).

The table below illustrates the link between human disease genes and C. elegans genes and their corresponding phenotypes. 

This table does not constitute a thorough list of genes and phenotypes for the diseases mentioned. For more information about worm genes associated with high-impact human diseases, start here.

Human diseaseOrganHuman GeneHuman phenotypeC. elegans geneC. elegans phenotypes
Aarskog–Scott syndromevariousFGD1distinctive facial features, mild to moderate short stature during childhood, sometimes heart defects exc-5endosome localization defects, excretory canal morphology defects, locomotion defects, organism morphology defects, sterility
AchondroplasiabonesFGFR3developmental delay, poorly defined organelles, short-limbed dwarfism, megalocephaly, spinal and facial deformity egl-15distinctive facial features, mild to moderate short stature during childhood, sometimes heart defects
Acute myeloid leukaemiamyeloid line of blood cellc-CBL (proto-oncogene)sli-1vulval lineage defects, larval lethality (when combined with let-23 mutation), low penetrance non-lethal head deformity.
Adrenoleukodystrophy, X-linkednervous system and the adrenal glandsALD pmp-4
Alagille Syndromeliver, heart, and other organs and body partsJAG1impaired differentiation of intrahepatic bile ducts, defects in heart, eye and kidney development.arg-1germ cell differentiation defect, accumulated germline cell corpses
Alcoholic liver disease and alcoholic cirrhosis aliverNCALDasymtomatic SMN patients with SMN-1 deletions have reduce expression of NCALDncs-1ameliorates pharyngeal pumping defects of smn-1 mutants
Alzheimer disease, type 4brainPS2memory loss, Neurofibrillary tangles, tau tangles, a-beta protein accumulation sel-12chemical hypersensitive, weakened neuromuscluar function, developmental defects
Amyotrophic lateral sclerosisbrain, spinal cordVAPB/ALS8/hVAPmuscle weakness, altered phosphorylation of neurofilaments, shortened life spanvpr-1actin organization defect, mis-positioning of specific head neurons, early lethality, sterile
Amyotrophic lateral sclerosisbrain, spinal cordSOD1muscle weakness, altered phosphorylation of neurofilaments, shortened life span sod-1myosin organization defect, egg laying defects, germ cell development defects, shortened life span, increased protein phosphorylation
AniridiaeyePAX6eye morphology defects, likely due to abnormal neuronal migration and misspecification of neurons. vab-3morphology defects, axon guidance defects, cell fate specification defects, dopaminergic fate atypical
Ataxia telangiectasiaimmune systemATMweak immune system, likely due to disturbed lymphocyte cell fate acquisition, delayed motor development, higher risk of cancer let-363delayed development, cell fate specification defects, adult growth defects, reduced cell proliferation, abnormal life span, tumor prolapse frequency decreased
Autoimmune polyglandular syndromeendocrine glandAIRET cell activation, proliferation and differentiation defect, muscle pain and cramping, weakness and fatigue let-418pharyngeal morphology defects, cell differentiation defects, cell fate transformation
Barth syndromeheartBTHSdilated cardiomyopathy, muscle weakness, recurrent infections due to small numbers of white blood cells, short stature. acl-3
Benign familial neonatal convulsionsbrainKCNQ2newborns show tonic-clonic seizures, sometimes changes of heart rate, respiration and systemic blood pressure kqt-1pharyngeal pumping arrhythmia
Bloom syndromevariousBLMdefective chromosomal disjunction at the end of meiosis, male sterility, predisposition to cancer and genomic instability him-6defective chromosomal disjunction, germline defects, male sterility, high incidence male progeny
Bor syndromeearEYA1hearing loss and other ear abnormalities, likely due to abnormal apoptosis of organ primordia eya-1apoptosis increased, body size defects, apoptosis increased, cell migration and apoptosis
Boston Type Craniosynostosiscranium, faceMSX2premature closure of coronal sutureCEH-24paralysis, reduced brood size, increased lethality, general sickness
Cancer bvariousRAS/RAF/MEK/ERKcell proliferation defect during developmentlet-60/lin-45/mek-, mpk-1vulva development impairment
Cancervarious ESPL1tumorigenesissep-1multinucleate cells, embryos fail to develop
CancervariousFOSmetastasisfos-1aanchor cell invasion into the vulval epithelium
Cancer cvariousRAS family (proto-oncogenes)improper signal transduction, proliferation and malignant transformationksraberrant cell specification (multivulva)
Cancers dvariousp53, BRCA1cancer (various)him gene familyhigh incidence of males
Cerebral cavernous malformationbrain, spinal cordCCM3/PDCD10cerebral cavernous malformationsccm-3excretory cell defect
Ceroid lipofuscinosis, infantile neuronalnervous systemINCLdevelopmental regression, decreased muscle tone, intellectual and motor disability, muscle twitches, epilepsy, brain atrophy, microcephaly, and vision loss ppt-1body morphology defect, locomotion, life span, increased thrashing
Chondrodysplasia punctatabonesARSEskeletal abnormalities, distinctive facial features, intellectual disability, and respiratory problems sul-2
ChoroideraemiaeyeCHMprogressive vision loss, ultimately leading to complete blindness haf-8
Citrullinaemia, adult onset type IIbloodSLC25A13accumulation of ammonia and other toxic substances in the blood K02F3.2sterile
Congenital adrenal hyperplasiaadrenal glandsCYP21constipation, decreased growth, enlarged genitalia cyp-33C4short defecation cycle, slow growth
Congenital nephrotic syndrome 1kidneysNPHS1abnormal muscle contractions due to loss of inhibition of motor neurons, high fat level in the blood and urine syg-2locomotion, fat accumulation, presynaptic vesicle cluster defects
Coronal craniosynostosiscranium, faceE proteins (TCF12)premature closure of coronal suturehlh-2cell fate specification and migration defect
Cyclic haematopoiesisblood cellsELA2blood-cell production from the bone marrow oscillates with 21-day periodicity. try-2dauer lifespan extended, sterile
Cystic fibrosis lungs, pancreas, liver, kidneys, and intestineCFTRdiagnostic before 1 year old, lethal within months without treatment; poor growth, poor weight gain, accumulation of mucus mrp-4embryonic lethal
Darier diseaseskinATPLA2dark crusty patches on the skin, sometimes containing pus. sca-1body wall muscle myosin organization defective, endoplasmic reticulum metabolism defects, shortened life span, morphology defect
Deafness, conductiveearPOU3F4deafness ceh-6gonad development, clear appearance, developmental defect, rectal development defects
Deafness, autosomal recessive 9earOTOFdeafness fer-1fertility defect, sperm defect
Deafness, neurosensory, autosomal recessive 3earMYO15profound deafness hum-6
Deficiency of coagulation factors V/VIIIbloodERGIC-53impaired blood coagulation ile-1
Dent diseasekidneysCLCN5damaged proximal tubules, abnormally large amount of proteins in the urine, kidney stones. clh-5muscle arm development defects, sterile
Diastrophic dysplasiavariousDTDabnormal morphology with short stature, joint pain and deformities restricting movement sulp-5
Dyskeratosis congenita, X-linkedvariousDKC1nail dystrophy, changes pigmentation). K01G5.5developmental delay postembryonic, sterility
Epidermolytic palmoplantar keratodermaskinKRT9thickening of the palms and soles associated with more generalized skin disorders mua-6epidermis cuticle detached, abnormally clear body, foraging behavior, growth defect, body muscle displaced, egg laying defects, developmental defect
FGFR-related craniosynostosis spectrumcranium, faceFGF receptors1,2 and 3premature closure of coronal sutureegl-15axon guidance defects, locomotion and egg laying defects
Fragile histidine triadesophageal, stomach, and colonFHITincreased resistance to DNA-damaging stressors like UVC lights; esophageal, stomach, and colon carcinomas nft-1organism UV resistant, germline defects
Fragile site mental retardation, type 2brain and other organsFMR2long and narrow face, large ears, flexible fingers, and large testicles, hyperactivity seizures F35A5.1
Friedreich ataxiabrainFRDAswallowing dysfunction, ATP content deficiency in lymphocytes, impaired muscle coordination and locomotion, nervous system damage frh-1feeding behavior defects, ATP levels reduced, locomotion defect, development defect, extended life span
Glycerol kinase deficiencyvariousGKaccumulation of glycerol in the blood and urine, vomiting and lethargy. R11F4.1
Gonadal dysgenesisreproductive systemSRYabsence of testis differentiation, progressive loss of germ cells on the embryo gonads, increased muscle mass in adult sox-2cell fate transformation, gonad defect, reduced brood size, locomotion defect, general sickness
Groenouw granular dystrophy, type 1eyes (cornea)BIGH3multiple small deposits in the superficial central corneal stroma, and progressive visual impairment, F26E4.7developmental defect, germline defects
Hereditary megaloblastic anaemiablood cellsCUBN fatigue, paleness of the skin, shortness of breath, light headedness, dizziness, fast or irregular heartbeat. ZC116.3slow growth, embryonic lethal, sterility
Hereditary multiple exostosesbonesEXT1develop multiple benign (noncancerous) bone tumors rib-1protruding vulva, pharyngeal development defects
Hereditary non-polyposis colon cancercolonMLH1 mlh-1spontaneous mutation rate increased, sterile, embryo lethality
Hermansky–Pudlak syndromeeyesHPSabnormally light coloring (pigmentation) of the skin, hair, and eyes apm-3
Holt–Oram syndromeheart, skeletonTBX5poor growth, skeletal abnormalities of upper limbs, easy fatigability with exercise, arrhythmias tbx-2slow growth, motor defects, pharyngeal (pumping organ) development defects, neuron development and migration defects
HyperekplexiabrainGLRA2pronounced startle responses to tactile or acoustic stimuli and hypertonia avr-14starvation enhance gustatory plasticity, locomotor coordination, chemotaxis
Hypophosphataemic rickets, X-linkedbonesXLHbone deformity including short stature and genu varum (bow leggedness).nep-11
Kallmann syndromevariousKALdelayed or absent puberty and an impaired sense of smell. K04F10.1
Long QT syndrome, type 1heartKVLQT1cardiac arrhythmia, seizures, increased frequency observed in inflammatory bowel disease kqt-3defecation cycle variable length, Bacillus thuringiensis toxin hypersensitive, long defecation cycle, pharyngeal pumpoiugn arrhythmia, pore forming toxin hypersensitive
Lowe syndromeeyeOCRLGermline mosaicism, involuntary, rapid eye movements, hypotonia, postnatal kidney defects and intellectual disability ocrl-1accumulated germline cell corpses, locomotion defect, early eggs laid, slow development,
Marfan syndromeheart, blood vessels, bones, joints, and eyesFBN1aortic enlargement, Long arms, legs and fingers,Chest sinks in or sticks out, Flexible joints fbn-1developmental defect, fertility defects, Fluorouracil resistant, locomotion defects, slow growth
Myotonic dystrophymusclesDMgradual muscle loss and weakness, muscles contraction defect, facial dysmorphia mrck-1locomotion defects, organism morphology defects, slow growth
Myotubular myopathyskeletal musclesMTM1muscle weakness, decreased muscle tone evident at birth. itsn-1protein subcellular localization defects
Nevoid basal cell carcinoma syndromevariousPTCdefects within multiple body systems (skin, nervous system, eyes, endocrine system, and bones) ptc-1avoids food, developmental defect, reduced fat content, morphology defect, fertility defects
Nigmegen breakage syndromevariousnibrinshort stature, an unusually small head size (microcephaly), distinctive facial features, recurrent respiratory tract infections, an increased risk of cancer, intellectual disability, and other health problems, immunodeficiency xnp-1accumulated germline cell corpses, everted vulva, gonad development defect
Non-syndromic deafness DFNA1earDIAPH1 hearing loss lgc-38
Opitz syndromeGenetic diseaseMID1ranging from mild intellectual disability and behavioural problems to lethal malformations arc-1
Pancreatic carcinomapancreasDPC4  jaundice, bloating, loss of appetite sma-4locomotion defects, organism morphology defects, multivulva
Parkinson disease juvenile 2brainPARKIN


protein aggregation, rigidity, resting tremor
reduction of mitochondrial complex I activity, disruption of the mitochondrial morphology, and impairment of protection of mitochondrial genomic integrity from oxidative stress.
protein aggregation, rigidity, resting tremor
reduced mitochondrial activity, disrupted mitochondrial morphology, reduced protection from oxidative stress, linked to manganese exposure
Parkinson’s diseasebrainLRRK2protein aggregation, muscular weakness, dopaminergic sigalling losslrk-1pesticide response
Polycystic kidney disease, type 1kidneyPKD1 erectile dysfunction in men, menstrual abnormalities in women, and decreased libido and fertility in both sexeslov-1male mating defects, locomotion and posture defect, increased girth, slow growth
Premature AgingvariousWRNdefective pigmentation, skin atrophy, loss of cutaneous fat, ulcerationwrn-1abnormally clear appearance, aging, cell cycle timing, growth rate, shortened larva
Retinitis pigmentosa 3, X-linkedeye (retina)RP3night blindness, field constriction, and pigmentary changes in the retina glo-4axon termination defective, fat content reduced, organelle morphology defects,
RetinoblastomaeyeRB1apoptosis defects, tumor formation, abnormal appearance of the retina lin-35reduced apoptosis, increased cell proliferation, egg laying defects, pharyngeal morphology defects, fertility and developmental defect,
Retinoschisis X-linked juvenileeyes (retina)XLRS1retinal morphological changes, impaired vision ddr-1lysosome-related organelle morphology defects, RAB-11 recycling endosome morphology defects
Rieger syndromevariousRIEGmaldevelopment of the neural crest cells, absent or under-developed teeth, craniofacial abnormalities, and abnormalities of the eye unc-30axon outgrowth defects, neuron morphology defects, locomotion defect
saethre-Chotzen Syndromecranium, faceTWIST familyNeural crest cell migration and function defecthlh-8muscle defects (egg laying defect, constipation)
SchizophreniabrainDISC1defects in neuronal connectivity during development, disorganized speech or behavior, and decreased participation in daily activities, difficulty with concentration and memory.none –> KI with  mDISC1axon guidance defects
Simpson–Golabi–Behmel syndromevariousGPC3infants larger than normal at birth unusual growth and weight gain gpn-1
Spinal muscular atrophybrain, spinal cordSMNprogressive motor neuron degeneration, muscle weakness smn-1slow growth, larval lethality, and impaired neuromuscular function in pharyngeal pumping during feeding
Spinocerebellar ataxia 2nervous systemSCA2uncoordinated movement, speech and swallowing difficulties, muscle wasting, slow eye movement, and sometimes dementia. atx-2developmental defects, germline defect
Stargardt diseaseeye (macula)ABCRprogressive damage—or degeneration—of the macula abt-4
T-cell acute lymphoblastic leukemiablood cellsNotch signalling increase in white blood cellsNotch signallingcell fate transformations
Thiamine-responsive megaloblastic anaemiavariousSLC19A2 hearing loss, diabetes, and blood  calledmegaloblastic anemia folt-2
Tuberous sclerosisGenetic diseaseTSC2 seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease.sipa-1
Velocardiofacial/DiGeorge Syndromecranium, face, brain and other organsTBX1 congenital heart problems, specific facial features, frequent infections, developmental delay, learning problems, and cleft palatemls-1uterine muscle cell fate specification defect
Waardenburg syndromevariousPAX3 deafness, white forelock (a frontal white blaze of hair), a difference of color between the iris of one eye and the other (heterochromia iridis), white eye lashes, and wide-set inner corners of the eyes. alr-1touch resistant
Wilms tumourkidneysWT1 klf-2locomotion defects
Wilson diseaseliver, brain and other vital organsWNDswelling, fatigue, abdominal pain, and uncontrolled or poorly coordinated movements cua-1aging defect, axon fasciculation defects, body wall muscle morphology defects, locomotion defects, paralyzed, shortened life span, slow growth
Wiskott–Aldrich syndromeWASPeczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). wsp-1cell migration failure, axon guidance defect
α1-antitrypsin deficiency (ATD)liverATM/ATZ fibrosis/cirrhosis and carcinogenesisnone –> KI with human ATM/ATZaggregation in Endoplasmic reticulum of intestinal cells, enhanced autophagy in ATZ animals


aThis is a fine example of how modifier mutations can be validated using different model organisms in which a given disease gene is being modeled.

bThe genetic pathways were practically identical: the tyrosine kinase growth factor receptor-Ras-Raf-MEK-MAPK pathway. the same set of orthologs is required for these three biological processes: vulval induction in C. elegans, eye development in D. melanogaster, and cell proliferation in mammalian cell culture.

cIdentification of the ksr gene in D. melanogaster and C. elegans in the mid-1990s. The discovery of this gene has great medical implications for cancer.

dCancer and the Him phenotype are both the result of chromosome segregation defects.

1. Neil S. Dhawan, Alex P. Scopton & Arvin C. Dar. Nature 537, 112–116 (01 September 2016).doi:10.1038/nature19327

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