large number of inferences for purine/pyrimidine metabolism

[ValWood]

MONDO:0019254

I'm not sure that all of these are errors in purine/pyrimidin metabolism

• | acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
  -- | --
    | slm3
• | adenine phosphoribosyltransferase deficiency
    | apt1
• | adenosine deaminase deficiency
    | dea2
• | adenylosuccinate lyase deficiency
    | ade8
• | AICA-ribosiduria
    | ade10
• | Arts syndrome
    | prs5, SPCC1620.06c
• | auditory neuropathy-optic atrophy syndrome
    | arh1
• | autosomal dominant mitochondrial myopathy with exercise intolerance
    | mix17
• | autosomal recessive ataxia due to ubiquinone deficiency
    | abc1
• | Bjornstad syndrome
    | bcs1
• | CAD-CDG
    | arg4
• | cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
    | sco1
• | cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
    | etp1
• | cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3
    | coa5
• | cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4
    | coa6
• | cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome
    | ism1
• | Charcot-Marie-Tooth disease recessive intermediate d
    | cox13
• | Charcot-Marie-Tooth disease type 4K
    | shy1
• | Charcot-Marie-Tooth disease X-linked recessive 5
    | prs5, SPCC1620.06c
• | coenzyme Q10 deficiency, primary, 1
    | ppt1
• | combined oxidative phosphorylation defect type 11
    | sif2
• | combined oxidative phosphorylation defect type 14
    | msf1
• | combined oxidative phosphorylation defect type 15
    | fmt1
• | combined oxidative phosphorylation defect type 17
    | trz2
• | combined oxidative phosphorylation defect type 2
    | mrps16
• | combined oxidative phosphorylation defect type 20
    | vrs1
• | combined oxidative phosphorylation defect type 21
    | SPAC24C9.09
• | combined oxidative phosphorylation defect type 23
    | mss1
• | combined oxidative phosphorylation defect type 24
    | slm5
• | combined oxidative phosphorylation defect type 25
    | msm1
• | combined oxidative phosphorylation defect type 26
    | trm5
• | combined oxidative phosphorylation defect type 4
    | tuf1
• | combined oxidative phosphorylation defect type 7
    | pth3
• | combined oxidative phosphorylation defect type 8
    | ala1
• | combined oxidative phosphorylation defect type 9
    | mrpl9
• | combined oxidative phosphorylation deficiency
    | mef1
• | combined oxidative phosphorylation deficiency 19
    | isd11, nfs1
• | combined oxidative phosphorylation deficiency 29
    | trx1
• | combined oxidative phosphorylation deficiency 33
    | mam33
• | combined oxidative phosphorylation deficiency 34
    | rsm7
• | combined oxidative phosphorylation deficiency 35
    | tit1
• | combined oxidative phosphorylation deficiency 36
    | mrp4
• | congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
    | erv2
• | cytochrome-c oxidase deficiency disease
    | cfh2, coa3, coa6, cox1, cox10, cox12, cox14, cox2, cox20, cox3, cox6, pet117, sco1, shy1, tac1
• | deafness-encephaloneuropathy-obesity-valvulopathy syndrome
    | dps1
• | Diamond-Blackfan anemia
    | rpl1801, rpl35, rps1902
• | Diamond-Blackfan anemia 1
    | rpl502, rps1901
• | Diamond-Blackfan anemia 10
    | rps2602
• | Diamond-Blackfan anemia 11
    | rpl26
• | Diamond-Blackfan anemia 12
    | rpl15
• | Diamond-Blackfan anemia 13
    | rps29
• | Diamond-Blackfan anemia 14 with mandibulofacial dysostosis
    | tsr2
• | Diamond-Blackfan anemia 15 with mandibulofacial dysostosis
    | rps2602, rps2802, tsr2
• | diamond-blackfan anemia 16
    | rpl2702
• | diamond-blackfan anemia 17
    | rps27
• | Diamond-Blackfan anemia 3
    | rps2402
• | Diamond-Blackfan anemia 4
    | rps1701
• | Diamond-Blackfan anemia 5
    | rpl35a
• | Diamond-Blackfan anemia 6
    | rpl502
• | Diamond-Blackfan anemia 7
    | rpl1102
• | Diamond-Blackfan anemia 8
    | rps7
• | Diamond-Blackfan anemia 9
    | rps1002
• | encephalopathy due to mitochondrial and peroxisomal fission defect
    | vps1
• | encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
    | coq9
• | erythrocyte AMP deaminase deficiency
    | ada1
• | familial steroid-resistant nephrotic syndrome with sensorineural deafness
    | coq6
• | fatal infantile hypertrophic cardiomyopathy due to mitochondrial complex I deficiency
    | SPAC9E9.15
• | fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
    | tsf1
• | glycogen storage disease due to phosphoglycerate kinase 1 deficiency
    | pgk1
• | glycogen storage disease VII
    | pfk1
• | gracile syndrome
    | bcs1
• | growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome
    | fsf1
• | hemolytic anemia due to diphosphoglycerate mutase deficiency
    | gpm1
• | hemolytic anemia due to glucophosphate isomerase deficiency
    | pgi1
• | hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
    | SPCC1827.03c
• | hereditary myopathy with lactic acidosis due to ISCU deficiency
    | isu1
• | hereditary spastic paraplegia 55
    | pth3
• | hereditary spastic paraplegia 77
    | msf1
• | hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
    | SPAC4G8.09
• | hyperinsulinism due to glucokinase deficiency
    | hxk2
• | hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome
    | dia4
• | hypoxanthine guanine phosphoribosyltransferase partial deficiency
    | hpt1
• | infantile hypertrophic cardiomyopathy due to MRPL44 deficiency
    | mrpl3
• | ITPA-related encephalopathy
    | ham1
• | Leber hereditary optic neuropathy
    | atp6, cob1, cox3
• | Leigh syndrome with leukodystrophy
    | aim22, coq11, etp1, fmt1, pda1, sdh1, shy1, tac1, SPAC11E3.12, SPBC18E5.10, SPCC417.16
• | Lesch-Nyhan syndrome
    | hpt1
• | lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome
    | oct1
• | leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
    | dar2
• | leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
    | mse1
• | MELAS syndrome
    | cox1, cox2
• | mitochondrial complex I deficiency
    | SPAC11E3.12, SPAC9E9.15, SPBC18E5.10
• | mitochondrial complex II deficiency
    | sdh1, sdh2, tim18, SPAC664.12c
• | mitochondrial complex III deficiency
    | cob1
• | mitochondrial complex III deficiency nuclear type 1
    | bcs1, qcr7
• | mitochondrial complex III deficiency nuclear type 3
    | qcr7
• | mitochondrial complex III deficiency nuclear type 4
    | qcr8
• | mitochondrial complex III deficiency nuclear type 5
    | qcr2
• | mitochondrial complex III deficiency nuclear type 6
    | cyt1
• | mitochondrial complex III deficiency nuclear type 8
    | mzm1
• | mitochondrial complex III deficiency nuclear type 9
    | cbp4
• | mitochondrial complex V (ATP synthase) deficiency nuclear type 2
    | SPAC1834.10c
• | mitochondrial complex V (ATP synthase) deficiency nuclear type 4
    | atp1
• | mitochondrial complex V (ATP synthase) deficiency, nuclear type 1
    | atp12
• | mitochondrial DNA deletion syndrome with progressive myopathy
    | dna2
• | mitochondrial DNA depletion syndrome 1
    | pog1
• | mitochondrial DNA depletion syndrome 12
    | anc1
• | mitochondrial DNA depletion syndrome 12a (cardiomyopathic type), autosomal dominant
    | anc1
• | mitochondrial DNA depletion syndrome 4a
    | pog1
• | mitochondrial DNA depletion syndrome 4b
    | pog1
• | mitochondrial DNA depletion syndrome 8a
    | suc22
• | mitochondrial DNA depletion syndrome 9
    | SPAC16E8.17c
• | mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria
    | lsc2
• | mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
    | ips1
• | mitochondrial myopathy with reversible cytochrome C oxidase deficiency
    | slm3
• | mitochondrial neurogastrointestinal encephalomyopathy
    | pog1, suc22
• | mitochondrial non-syndromic sensorineural deafness
    | cox1
• | mitochondrial non-syndromic sensorineural deafness with susceptibility to aminoglycoside exposure
    | cox1, slm3
• | mitochondrial proton-transporting ATP synthase complex deficiency
    | atp6, atp8
• | multiple mitochondrial dysfunctions syndrome 1
    | nfu1
• | multiple mitochondrial dysfunctions syndrome 2
    | fra3
• | multiple mitochondrial dysfunctions syndrome 3
    | iba57
• | multiple mitochondrial dysfunctions syndrome 4
    | isa2
• | multiple mitochondrial dysfunctions syndrome 5
    | isa1
• | multiple mitochondrial dysfunctions syndrome 6
    | qcr1
• | myopathy due to myoadenylate deaminase deficiency
    | ada1
• | myopathy, lactic acidosis, and sideroblastic anemia 1
    | pus3, SPCC576.06c
• | myopathy, lactic acidosis, and sideroblastic anemia 2
    | SPCC576.06c
• | myopathy, lactic acidosis, and sideroblastic anemia 3
    | atp6
• | NARP syndrome
    | atp6
• | Navajo neurohepatopathy
    | sym1, SPAC3G6.05
• | neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
    | coq4
• | neonatal severe cardiopulmonary failure due to mitochondrial methylation defect
    | pet802
• | optic atrophy 3
    | opa3
• | orotic aciduria
    | ura5
• | pancreatic insufficiency-anemia-hyperostosis syndrome
    | cox5
• | periodic paralysis with later-onset distal motor neuropathy
    | atp6, atp8
• | Perrault syndrome 2
    | hrs1
• | Perrault syndrome 4
    | SPAC4G8.09
• | phosphoribosylpyrophosphate synthetase superactivity
    | SPCC1620.06c
• | pontocerebellar hypoplasia type 6
    | mrs1
• | primary coenzyme Q10 deficiency 8
    | coq7
• | progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 1
    | pog1
• | progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2
    | anc1
• | progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5
    | suc22
• | progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
    | pog1
• | progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
    | rnh1, suc22
• | purine nucleoside phosphorylase deficiency
    | SPAC1805.16c
• | pyruvate kinase deficiency of red cells
    | pyk1
• | Sengers syndrome
    | anc1
• | severe X-linked mitochondrial encephalomyopathy
    | aif1
• | spastic ataxia 3
    | msm1
• | spastic ataxia 4
    | cid11
• | spastic ataxia 5
    | yta12
• | spinocerebellar ataxia type 28
    | yta12
• | spinocerebellar ataxia with epilepsy
    | pog1
• | triosephosphate isomerase deficiency
    | tpi1
• | X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome
    | SPCC1620.06c

[ValWood]

I don't have time to go through them all but for example

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (MONDO:0011451)

glycogen storage diseases look odd too

and some of the aneamias, for example
hemolytic anemia due to glucophosphate isomerase deficiency

I can see where this comes from
for example glycolysis will make ATP from ADP, but would people consider this to be an error in purine/pyrimidine metabolism?
I would expect these to be restricted to the pathways of purine and pyrimidine metabolism?

[ValWood]

We just mapped from DO to Mondo and the number of purine/pyrimidine disorders for fission yeast has gone up from 3->152

[nicolevasilevsky]

Can anyone weigh in on this?

@cmungall @pnrobinson

I'm not sure how to address this.

Here is the explanation for cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 (MONDO:0011451)

[ValWood]

Actually, although it seems a bit odd to me I think it's oK to live with the "oxidative phosphorylation " ones as this could be classed as a defect in "purine or pyrimidine metabolism" although it's really the 'interconversion of the pool or ATP and ADP'. This is probably really a GO issue and one not yet fully resolved.

So the one that stands out for me otherwise is
Diamond-Blackfan anemia.
Most causes of this are cytosolic ribosome defects so any issue with pyrimidine metabolism seems more of a symptom than a cause.

[ValWood]

Although maybe you could remove the relation between

mitochondrial oxidative phosphorylation disorder (MONDO:0016387)

and

MONDO:0019254
Disease association
inborn disorder of purine or pyrimidine metabolism (MONDO:0019254)

because for many of these the look quite strange

MONDO:0054865
Disease association
encephalopathy due to mitochondrial and peroxisomal fission defect
for example, is due to defects in GTPase motors for mitochondrial fission and fusion
is classed as a disease of pyrimidine metabolism via
mitochondrial oxidative phosphorylation disorder with no known mechanism

[nicolevasilevsky]

[ValWood]

@cmungall @pnrobinson
I get
https://www.pombase.org/term_genes/MONDO:0019254
it seems wrong to have
cytosolic ribosomal proteins and some others described as "disorders of pyrimidine/pyrimidine metabolism"
(I'm pretty sure that the ortholog calls are all correct)

[ValWood]

so for example
Diamond-Blackfan anaemia (MONDO:0015253) (which is caused by mutations in many cytosolic ribosomal proteins)
somehow maps to "disorders of pyrimidine/pyrimidine metabolism"
Maybe that is correct but it was a red flag to me based on my knowledge....

[pnrobinson]

@ValWood I agree
@cmungall @nicolevasilevsky This is an authoratative source on metabolic disorders. I would suggest that we largely adopt this hierarchy

http://evm.health2media.com/#/detail-view/disorder/0/4