Exposure to SARS-CoV-2 and Infantile Diseases

Keywords

SARS-CoV-2 spike gp - molecular mimicry - peptide sharing - cross-reactivity - immunologic imprinting - autoimmune - infantile diseases

Introduction

Recently, researchers and clinicians called attention on the issue of vaccinating newborns and children against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to protect from coronavirus disease 2019 (COVID-19). Pros and cons have been examined and discussed in light of the following data:

• Children account only for 1.7 to 2% of the diagnosed cases of COVID-19.[1]

• COVID-19 in children shows a milder disease course and better prognosis than adults. Mortality is extremely low.[2]

• COVID-19 is deadlier for aged people than for other age groups.[3]

• Severe manifestations of COVID-19 in adults comprehend dyspnea, respiratory failure, pneumonitis, thromboembolic events, cardiogenic shock, renal injury, ischemic strokes, encephalitis, and cutaneous eruptions.[4]

• In contrast, severe manifestations of COVID-19 in children appear to be associated only with an uncommon, somewhat serious but tractable inflammatory disorder, that is, the so-called multisystem inflammatory syndrome in children (MIS-C). MIS-C is rarest and rarely is fatal. Indeed, Ergenc et al[5] reported that among 1,340 patients aged between 0 and 216 months and diagnosed with COVID-19, only 6 patients had MIS-C, which corresponds to a MIS-C incidence of 0.4%. None of the patients died. In parallel, Payne et al[6] reported that MIS-C incidence per 1,000,000 SARS-CoV-2 infections was 316.

• Moreover, and crucially, an analysis of the potential risk of autoimmune cross-reactivity[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] lacks while it should be compulsorily included in the benefit–risk assessment of SARS-CoV-2 vaccination in children.

Then, the present study aims at exploring (or excluding) the possibility that molecular mimicry and the consequent potential cross-reactivity may exist between SARS-CoV-2 and human proteins that are linked, when altered, to infantile diseases, so that targeting the viral antigen via vaccination might equate to hit human proteins linked to childhood pathologies.

Materials and Methods

Peptide sharing between SARS-CoV-2 spike glycoprotein (gp) (NCBI, GenBank Protein Accession Id = QHD43416.1) from SARS-CoV-2 and human proteins related to childhood diseases was analyzed as previously detailed[9] [10] using the pentapeptide as minimal immune determinant unit. Pentapeptides were used as sequence probes since a peptide grouping composed of five amino acid (aa) residues defines a minimal immune unit that can (1) induce highly specific antibodies and (2) determine antigen–antibody-specific interaction.[18] [19] A library of 372 human proteins linked—when altered—to pediatric diseases was obtained from UniProt database (www.uniprot.org)[20] using the keyword “infantile.” The 372 proteins are listed in [Supplementary Table S1] (online only).

CoV controls were as follows, with NCBI:txid number in parentheses: Middle East respiratory syndrome (MERS)-CoV (1335626); human (H) CoV-229E (11137); HCoV-NL63 (277944).

Methodologically, the SARS-CoV-2 spike gp primary aa sequence was dissected into pentapeptides offset each other by one residue (i.e., MFVFL, FVFLV, VFLVL, FLVLL, and so forth) and the resulting viral pentapeptides were analyzed for occurrences within the human proteins related to infantile diseases. Peptide Match and Peptide Search programs available at www.uniprot.org²⁰ were used.

The immunologic potential of the peptides shared between SARS-CoV-2 spike gp and proteins related to childhood diseases was analyzed by searching the Immune Epitope Database (IEDB, www.iedb.org/)²¹ for immunoreactive SARS-CoV-2 spike gp-derived epitopes hosting the shared pentapeptides.

Finally, pentapeptides common to SARS-CoV-2 spike gp–derived epitopes and human proteins related to infantile diseases were additionally controlled for occurrences in the following bacterial pathogens listed with NCBI:txid number in parentheses: Bordetella pertussis (257313), Corynebacterium diphtheriae (257309), Clostridium tetani (212717), Haemophilus influenzae (71421), and Neisseria meningitides (122586).

Results and Discussion

Molecular Mimicry between SARS-CoV-2 Spike gp and Human Proteins Related to Infantile Diseases

[Table 1] shows that SARS-CoV-2 spike gp shares a high number of minimal immune determinants (namely, 54) with 43 human proteins that associate with infantile disorders when altered, mutated, or, however, improperly functioning. The following points emerge from [Table 1]:

Table 1 Peptide sharing between SARS-CoV-2 spike gp and human proteins related to infantile diseases

Peptides[a]	Human proteins, pathologies, and references[b]
TECSN	ANTR2. Anthrax toxin receptor 2 Juvenile hyaline fibromatosis and infantile systemic hyalinosis[22]
GAGAAA	ARX. Homeobox protein ARX Lissencephaly associated with abnormal genitalia[23]
DIAAR	AT1A2. Sodium/potassium-transporting ATPase subunit α-2 Alternating hemiplegia of childhood. Epilepsy[24] [25]
SFELL	CLN6. Ceroid-lipofuscinosis neuronal protein 6 Seizures, dementia, visual loss, and/or cerebral atrophy[26]
NSVAY	CO1A1. Collagen α-1(I) chain Osteogenesis imperfecta/Ehlers–Danlos' syndrome[27]
TLLAL	COX15. Cytochrome c oxidase assembly protein homolog Microcephaly, encephalopathy, hypertrophic cardiomyopathy, lactic acidosis, respiratory distress, hypotonia and seizures[28]
FLLKY	CTNS. Cystinosin Late-onset juvenile or adolescent nephropathic cystinosis[29]
NLLLQ, VPVAI, AGTIT	DPOG1. DNA polymerase subunit gamma-1 Juvenile-onset Alpers' syndrome and status epilepticus[30]
SEPVL	FRMD7. FERM domain-containing protein 7 Infantile nystagmus syndrome[31]
EDLLF, LQELGK	GLSK. Glutaminase kidney isoform, mitochondrial Neonatal epileptic encephalopathy[32]
SSVLN	HCN1. Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 Infantile epileptic encephalopathy[33]
YLQPR	MTU1. Mitochondrial tRNA-specific 2-thiouridylase 1 Mitochondrial infantile liver disease[34]
SLLIV	NALCN. Sodium leak channel nonselective protein Hypotonia, speech impairment, intellectual disability, pyramidal signs, and chronic constipation[35]
IAGLI, VDCAL, LLQYG	NBAS. Neuroblastoma-amplified sequence Growth retardation, senile face, and optic atrophy[36]
GVVFL	NEUR1. Sialidase-1 Sialidosis: cherry red macular spots in childhood, progressive debilitating myoclonus, insidious visual loss[37]
VCGPK, NASVV	NPC1. NPC intracellular cholesterol transporter 1 Infantile Niemann–Pick type C disease[38]
LVLLPL	NPT2A. Sodium-dependent phosphate transport protein 2A Hypercalcemia, failure to thrive, vomiting, nephrocalcinosis[39]
GGFNF, AGAAA	NUP62. Nuclear pore glycoprotein p62 Infantile bilateral striatal necrosis[40]
EMIAQ, LVDLP	OPA1. Dynamin-like 120 kDa protein, mitochondrial Lethal encephalopathy, cardiomyopathy optic atrophy[41]
KSFTV	PCD19. Protocadherin-19 Seizure, cognitive impairment, and delayed development of variable severity. Mainly affects females[42]
EVRQI, KVTLA	PEX1. Peroxisome biogenesis factor 1 The peroxisome biogenesis disorders include: Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and rhizomelic chondrodysplasia punctata[43]
SASFS, FLVLLP	PEX12. Peroxisome assembly protein 12 See above[43]
VLLPL	PEX26. Peroxisome assembly protein 26 See above[43]
LHSTQD	PEX6. Peroxisome assembly factor 2 See above[43]
LIAIV	PIGP. Phosphatidylinositol N-acetylglucosaminyltransferase subunit P Developmental and epileptic encephalopathy[44]
LQPEL	PRRT2. Proline-rich transmembrane protein 2 Recurrent and brief attacks of abnormal involuntary movements, triggered by sudden voluntary movement[45]
QIAPG	PTH2. Peptidyl-tRNA hydrolase 2, mitochondrial Global developmental delay, hypotonia, hearing loss, ataxia, hyporeflexia, hypothyroidism, and pancreatic insufficiency[46]
DLFLP	RMND1. Required for meiotic nuclear division protein 1 Neonatal hypotonia and lactic acidosis. Affected individuals may have respiratory insufficiency, seizures[47]
KRVDF	RPB1. DNA-directed RNA polymerase II subunit RPB1 Hypotonia and intellectual and behavioral abnormalities[48]
PGDSS	SC6A3. Sodium-dependent dopamine transporter Infantile parkinsonism-dystonia[49]
NLAAT	SCN1A. Sodium channel protein type 1 subunit α Generalized epilepsy with febrile seizures persisting beyond the age of 6 y and/or a variety of afebrile seizure types[50]
NLAAT	SCN2A. Sodium channel protein type 2 subunit α Benign infantile epilepsy[51]
NLAAT	SCN3A. Sodium channel protein type 3 subunit α Epilepsy with focal seizures arising from temporal, frontal, parietal, occipital lobes[52]
NLAAT, DPLSE	SCN8A. Sodium channel protein type 8 subunit α Delayed cognitive and motor development, attention deficit disorder, and cerebellar ataxia[53]
VVLSF, NLDSK	SIAT6. CMP-N-acetylneuraminate-β-1,4-galactoside α-2,3-sialyltransferase Significantly below average general intellectual functioning associated with impairments in adaptive behavior[54]
LQPRT	SIAT9. Lactosylceramide α-2,3-sialyltransferase Salt and pepper syndrome with seizures, psychomotor delay, cortical blindness. Patches of skin hypo- or hyperpigmentation[55]
QSLLI	SLF2. SMC5-SMC6 complex localization factor protein 2 Infantile-onset spinocerebellar ataxia[56]
GRLQS	SPTN2. Spectrin β chain, nonerythrocytic 2 Spinocerebellar ataxia[57]
SASFST	STXB1. Syntaxin-binding protein 1 Developmental and epileptic encephalopathy[58]
FIAGL	SUCA. Succinate-CoA ligase subunit α, mitochondrial Infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration[59]
LADAG	SYLC. Leucine–tRNA ligase, cytoplasmic Infantile liver failure syndrome[60]
LPLVS	SZT2. KICSTOR complex protein SZT2 Developmental and epileptic encephalopathy[61]
DSLSS	TPP1. Tripeptidyl-peptidase 1 Spinocerebellar ataxia[62]

Abbreviations: gp, glycoprotein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^a Hexapeptides derived from overlapping pentapeptides are given in bold.

^b Human proteins given by UniProt entry and name are in italic. Further details and references on related pathologies are available in PubMed, OMIM, and UniProt databases.

• The unexpectedly high molecular mimicry described in [Table 1] and the consequent potential cross-reactivity support the hypothesis that several diseases might occur in children following exposure to the SARS-CoV-2 antigen.

• Mathematically, the vastness of the common molecular platform stands out when one considers that the probability for 2 proteins to share 1 pentapeptide on the basis of the 20 aa and neglecting the relative aa abundance is equal to 1 out of 20 raised to 5. That is, it is equal to 0.0000003125.

• Such unexpected massive peptide commonality between SARS-CoV-2 antigen gp and the human proteome indicates and confirms a strict phenetic relationship between viruses and the origin of eukaryotic cells according to the endosymbiotic theory.[63]

• Pathologically, the diseasome that might occur via cross-reactivity includes severe disorders such as nephropathies, seizures, cardiomyopathies, parkinsonism-dystonia, global developmental delay, hypotonia, hearing loss, ataxia, hyporeflexia, hypothyroidism, pancreatic insufficiency, and lethal encephalopathy, inter alia.

Immunologic Potential of the Peptide Sharing between SARS-CoV-2 Spike gp and Human Proteins Related to Infantile Diseases

The cross-reactivity potential of the peptide sharing described in [Table 1] appears to be supported by inspection of IEDB (www.iedb.org).[21] Indeed, all the 54 minimal immune determinants common to SARS-CoV-2 spike gp and human proteins related to infantile diseases occur and repeatedly recur in 839 SARS-CoV-2 spike gp–derived epitopes, of which [Table 2] displays only a synopsis in the interest of brevity. In essence, [Table 2] validates, likely enough, the cross-reactivity hypothesis at the basis of the present study.

Table 2 Immunoreactive SARS-CoV-2 spike gp-derived epitopes containing pentapeptides shared between SARS-CoV-2 spike gp and human proteins linked to infantile diseases: a synopsis

IEDB ID[a]	Epitope sequence[b]	IEDB ID[a]	Epitope sequence[b]
3589	aphGVVFLhv	1325536	tLADAGfik
4321	asaNLAATk	1327418	vydpLQPELdsf
16156	FIAGLIAIV	1327824	wtAGAAAyy
23200	GVVFLhvty	1327836	wtfGAGAAl
36724	litGRLQSl	1329248	dEMIAQytsal
37289	llfnKVTLA	1330227	tqDLFLPff
37724	LLQYGsfct	1330420	aphGVVFL
50166	pyrvVVLSF	1330526	lynSASFSTf
51999	qpyrvVVLSF	1331519	EDLLFn
57592	SEPVLkgvkl	1332003	fvFLVLLPL
57792	sfiEDLLFnk	1332424	itGRLQSlqty
59161	slidLQELGK	1332664	lltdEMIAQy
71996	vydpLQPEL	1332702	LQELGKyeqy
1074967	lepLVDLPi	1332727	ltdEMIAQyt
1075065	stqDLFLPff	1332785	mfvFLVLLPLVSs
1309147	YLQPRTfll	1333450	SASFSTfkcy
1310623	ltdEMIAQy	1333520	SFELLhapatv
1311673	EVRQIAPGqt	1333523	sfiEDLLF
1311846	SFELL	1333568	sKRVDFcgkgy
1313244	nSASFSTfk	1333801	sTECSNLLLQy
1314425	alDPLSEtk	1333812	stqDLFLPf
1315940	epLVDLPi	1333921	tdEMIAQy
1316323	fdeddSEPVL	1334182	vgYLQPRTf
1317916	gYLQPRTfll	1390229	VDCALDPLSEtkctlks
1320443	lgaeNSVAY	1541124	KRVDFcgk
1321078	LPLVSsqcv	1546420	fiEDLLFnk
1322298	NASVVniqk	1547648	gYLQPRTfl
1323200	QELGKyeqy	1593850	YLQPRifll
1323249	QIAPGqtgk	1597683	fiEDLLFnkv
1323750	rasaNLAATk	1625440	ssvLHSTQ
1325401	TECSNLLLQy	1659240	fvFLVLLPLv

Abbreviations: gp, glycoprotein; IEDB, Immune Epitope Database; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

^a Epitopes listed according to the IEDB ID number. Details and references for each epitope are available at www.iedb.org/.²¹

^b Shared peptides are given capitalized.

Specificity of the Peptide Sharing between SARS-CoV-2 Spike gp and Human Proteins Linked to Infantile Diseases

To control the specificity of the peptide sharing between SARS-CoV-2 spike gp and human proteins linked to childhood diseases ([Table 1]), the 54 shared pentapeptides were analyzed for occurrences in other coronaviruses not associated with particular pediatric complications, that is, MERS-CoV, HCoV-OC43, and HCoV-229E. Results are shown in [Table 3] that provides evidence that the intense peptide overlap between SARS-CoV-2 spike gp and human proteins related to childhood diseases is highly specific. De facto, almost all the 54 shared pentapeptides are absent in the CoV controls, that is, in the pathogenic MERS-CoV[64] as well as in the scarcely pathogenic HCoV-OC43 and HCoV-229E that cause only mild symptoms.[65]

Table 3 Quantitation of the pentapeptide sharing between CoVs spike gps and human proteins linked to childhood diseases

Spike gp from:	Number of shared pentapeptides
SARS-CoV-2	54
MERS-CoV	−
hCoV-229E	−
hCoV-NL63	2

Abbreviations: CoV, coronavirus; gp, glycoprotein; h, human; MERS, Middle East respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Occurrence in Bacteria of Peptides Common to SARS-CoV-2 Spike gp and Proteins Linked to Infantile Diseases

To further control the specificity of the peptide sharing between SARS-CoV-2 spike gp and human proteins linked to childhood diseases, comparative sequence analyses were extended to the bacterial pathogens B. pertussis, C. diphtheriae, C. tetani, H. influenzae, and N. meningitides—that is, bacteria to which children may be exposed also following current vaccinal routes—were analyzed. Results are displayed in [Table 4].

Table 4 Occurrences in bacterial pathogens of pentapeptides shared between SARS-CoV-2 spike gp and human proteins linked to infantile diseases

Organism	Shared pentapeptides
B. pertussis	AGAAA, AGTIT, DIAAR, DSLSS, FIAGL, FLVLL, GAGAA, GVVFL, KVTLA, LADAG, LIAIV, LPLVS, LQELG, LVDLP, NASVV, NLAAT, QELGK, SLLIV, VLLPL
C. diphtheriae	AGAAA, AGTIT, GAGAA, LADAG, VPVAI
C. tetani	AGAAA, AGTIT, DLFLP, EVRQI, FIAGL, LLQYG, LQELG, NASVV, SSVLN
H. influenzae	AGAAA, AGTIT, DIAAR, EVRQI, GAGAA, GGFNF, GVVFL, IAGLI, KRVDF, LADAG, LIAIV, LPLVS, LQELG, LVDLP, LVLLP, NASVV, NLAAT, NLDSK, NLLLQ, NSVAY, QELGK, QIAPG, QSLLI, SFELL, SLLIV, SSVLN, TLLAL, VLLPL, VPVAI, VVLSF
N. meningitidis	AGAAA, ASFST, EVRQI, FIAGL, FLVLL, GAGAA, KRVDF, LADAG, LQELG, LQPEL, NLDSK, QELGK, TLLAL, VLLPL, VVLSF

Abbreviations: gp, glycoprotein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

It can be seen that many of the 54 peptides shared between SARS-CoV-2 spike gp and human proteins linked to infantile diseases also occur in the analyzed microbial organisms, thus highlighting that, contrary to expectations, while practically no phenetic similarity exists between SARS-CoV-2 spike gp and the control CoVs ([Table 3]), a high level of similarity exists between SARS-CoV-2 spike gp and bacterial pathogens to which children have been exposed via passive/active infection and by which the immune system has already been imprinted ([Table 4]).

Then, as highlighted in the literature,[66] [67] [68] [69] [70] [71] [72] the interpathogen peptide commonality can add a further potential burden to the molecular mimicry phenomenon described in [Table 1]. Indeed, a fundamental property of the immune system is the memory for immune determinants previously encountered so that, as a rule, the immune system reacts by recalling memory of the responses toward past infections rather than producing ex novo responses toward the recent ones.

Consequently, in the case under study here, the following sequence of events may unfold:

• A primary response to SARS-CoV-2 can actually occur as a secondary (or even tertiary) response against pathogens previously encountered and memorized by the immune system. That is, anamnestic secondary antibacterial responses can occur after exposure to SARS-CoV-2. Such anamnestic secondary antibacterial responses will be of considerable proportions given the extent of the viral versus bacterial peptide overlap described in [Table 4].

• SARS-CoV-2 antigen will not be affected in that the immunologic memory deflects the immune response toward the already encountered peptides, that is, the bacterial peptide platform detailed in [Table 4].

• However, also the attack against the early sensitizing bacterial pathogens can fail by being the early sensitizing bacterial pathogens no more present in the organism.

• Then, the ultimate result might be that the anamnestic, high affinity, high avidity, and extremely potent secondary immune response elicited by the lastly encountered pathogen—that is, SARS-CoV-2—can hit the only available targets, that is, the common immune determinants that in this instance are present in the human proteins related to infantile diseases ([Table 1]).

According to this sequence of events, molecular mimicry and immunologic memory might explain also the different pathological outcomes of the autoimmune responses—from mild symptoms to even lethal pathologies—that may follow exposure to SARS-CoV-2. In practice, the history of infections/immunization of each child is the main factor dictating the onset and the severity of the pathologies outlined in [Table 1].

Conclusion

The present study investigates the possible adverse events that might occur in newborns and children following exposure to SARS-CoV-2. Based on the extensive peptide sharing between SARS-CoV-2 gp antigen and human proteins related to infantile diseases, supported by epitopic data that confer a high immunoreactivity to the peptide sharing, and given the possibility of immunologic imprinting phenomena, this study leads to predict that exposing newborns and children to SARS-CoV-2 might associate with infantile severe diseases such as growth retardation, abnormal genitalia, epilepsy, seizures, cardiomyopathies, hypotonia, visual loss, hypercalcemia, ataxia, infantile parkinsonism-dystonia, below average general intellectual functioning, encephalopathies, and inter alia. Then, the present data suggest that extreme caution be exercised in planning and implementing a mass anti-SARS-CoV-2 vaccination of infants and children.

• References

• 1 Kapustova L, Petrovicova O, Banovcin P. et al. COVID-19 and the differences in physiological background between children and adults and their clinical consequences. Physiol Res 2021; 70 (S2): S209-S225
• 2 Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr 2020; 109 (06) 1088-1095
• 3 Islam MS, Larpruenrudee P, Saha SC. et al. How severe acute respiratory syndrome coronavirus-2 aerosol propagates through the age-specific upper airways. Phys Fluids 2021; 33 (08) 081911
• 4 Ladani AP, Loganathan M, Kolikonda MK, Lippmann S. COVID-19 Legacy. South Med J 2021; 114 (12) 751-759
• 5 Ergenc Z, Kepenekli E, Çetin E. et al. Incidence of multisystem inflammatory syndrome in children and the comorbidity scores in pediatric coronavirus disease 2019 cases. Pediatr Int (Roma) 2022; 64 (01) e15084
• 6 Payne AB, Gilani Z, Godfred-Cato S. et al; MIS-C Incidence Authorship Group. Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw Open 2021; 4 (06) e2116420
• 7 Chen Y, Xu Z, Wang P. et al. New-onset autoimmune phenomena post-COVID-19 vaccination. Immunology 2022; 165 (04) 386-401
• 8 Churilov LP, Kanduc D, Ryabkova VA. COVID-19: adrenal response and molecular mimicry. Isr Med Assoc J 2021; 23 (10) 618-619
• 9 Kanduc D. From anti-SARS-CoV-2 immune responses to COVID-19 via molecular mimicry. Antibodies (Basel) 2020; 9 (03) 33
• 10 Kanduc D. From anti-SARS-CoV-2 immune response to the cytokine storm via molecular mimicry. Antibodies (Basel) 2021; 10 (04) 36
• 11 Angileri F, Legare S, Marino Gammazza A, Conway de Macario E, Jl Macario A, Cappello F. Molecular mimicry may explain multi-organ damage in COVID-19. Autoimmun Rev 2020; 19 (08) 102591
• 12 Garg RK, Paliwal VK. Spectrum of neurological complications following COVID-19 vaccination. Neurol Sci 2022; 43 (01) 3-40
• 13 Gambichler T, Boms S, Susok L. et al. Cutaneous findings following COVID-19 vaccination: review of world literature and own experience. J Eur Acad Dermatol Venereol 2022; 36 (02) 172-180
• 14 Mehta SK, Sunder A. Getting paralysed after COVID: Guillain-Barre syndrome. J Family Med Prim Care 2021; 10 (07) 2706-2708
• 15 Moody R, Wilson K, Flanagan KL, Jaworowski A, Plebanski M. Adaptive immunity and the risk of autoreactivity in COVID-19. Int J Mol Sci 2021; 22 (16) 8965
• 16 Chittal A, Rao S, Lakra P, Nacu N, Haas C. A case of COVID-19 vaccine-induced thrombotic thrombocytopenia. J Community Hosp Intern Med Perspect 2021; 11 (06) 776-778
• 17 Shi H, Zuo Y, Navaz S. et al. Endothelial cell-activating antibodies in COVID-19. Arthritis Rheumatol 2022; 74 (07) 1132-1138
• 18 Kanduc D. Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020; 87 (04) 268-276
• 19 Kanduc D. The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021; 18 (03) 177-184
• 20 UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res 2019; 47 (D1): D506-D515
• 21 Vita R, Mahajan S, Overton JA. et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res 2019; 47 (D1): D339-D343
• 22 Hanks S, Adams S, Douglas J. et al. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet 2003; 73 (04) 791-800
• 23 Kato M, Das S, Petras K. et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 2004; 23 (02) 147-159
• 24 Swoboda KJ, Kanavakis E, Xaidara A. et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 2004; 55 (06) 884-887
• 25 Deprez L, Weckhuysen S, Peeters K. et al. Epilepsy as part of the phenotype associated with ATP1A2 mutations. Epilepsia 2008; 49 (03) 500-508
• 26 Gao H, Boustany RM, Espinola JA. et al. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet 2002; 70 (02) 324-335
• 27 Cabral WA, Makareeva E, Colige A. et al. Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Biol Chem 2005; 280 (19) 19259-19269
• 28 Alfadhel M, Lillquist YP, Waters PJ. et al. Infantile cardioencephalopathy due to a COX15 gene defect: report and review. Am J Med Genet A 2011; 155A [phone]
• 29 Attard M, Jean G, Forestier L. et al. Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. Hum Mol Genet 1999; 8 (13) 2507-2514
• 30 Uusimaa J, Hinttala R, Rantala H. et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia 2008; 49 (06) 1038-1045
• 31 Bai D, Shi W, Qi Z. et al. Clinical feature and waveform in infantile nystagmus syndrome in children with FRMD7 gene mutations. Sci China Life Sci 2017; 60 (07) 707-713
• 32 Rumping L, Büttner B, Maier O. et al. Identification of a loss-of-function mutation in the context of glutaminase deficiency and neonatal epileptic encephalopathy. JAMA Neurol 2019; 76 (03) 342-350
• 33 Nava C, Dalle C, Rastetter A. et al; EuroEPINOMICS RES Consortium. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet 2014; 46 (06) 640-645
• 34 Gaignard P, Gonzales E, Ackermann O. et al. Mitochondrial infantile liver disease due to TRMU gene mutations: three new cases. JIMD Rep 2013; 11: 117-123
• 35 Al-Sayed MD, Al-Zaidan H, Albakheet A. et al. Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay. Am J Hum Genet 2013; 93 (04) 721-726
• 36 Maksimova N, Hara K, Nikolaeva I. et al. Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. J Med Genet 2010; 47 (08) 538-548
• 37 Bonten E, van der Spoel A, Fornerod M, Grosveld G, d'Azzo A. Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev 1996; 10 (24) 3156-3169
• 38 Blom TS, Linder MD, Snow K. et al. Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Hum Mol Genet 2003; 12 (03) 257-272
• 39 Magen D, Berger L, Coady MJ. et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. N Engl J Med 2010; 362 (12) 1102-1109
• 40 Basel-Vanagaite L, Muncher L, Straussberg R. et al. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol 2006; 60 (02) 214-222
• 41 Spiegel R, Saada A, Flannery PJ. et al. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet 2016; 53 (02) 127-131
• 42 Depienne C, Bouteiller D, Keren B. et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet 2009; 5 (02) e1000381
• 43 Yik WY, Steinberg SJ, Moser AB, Moser HW, Hacia JG. Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. Hum Mutat 2009; 30 (03) E467-E480
• 44 Johnstone DL, Nguyen TT, Murakami Y. et al; Care4Rare Canada Consortium. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Hum Mol Genet 2017; 26 (09) 1706-1715
• 45 Li M, Niu F, Zhu X. et al. PRRT2 mutant leads to dysfunction of glutamate signaling. Int J Mol Sci 2015; 16 (05) 9134-9151
• 46 Hu H, Matter ML, Issa-Jahns L. et al. Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Ann Clin Transl Neurol 2014; 1 (12) 1024-1035
• 47 Garcia-Diaz B, Barros MH, Sanna-Cherchi S. et al. Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation. Am J Hum Genet 2012; 91 (04) 729-736
• 48 Haijes HA, Koster MJE, Rehmann H. et al. De novo heterozygous POLR2A variants cause a neurodevelopmental syndrome with profound infantile-onset hypotonia. Am J Hum Genet 2019; 105 (02) 283-301
• 49 Kurian MA, Zhen J, Cheng SY. et al. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J Clin Invest 2009; 119 (06) 1595-1603
• 50 Harkin LA, McMahon JM, Iona X. et al; Infantile Epileptic Encephalopathy Referral Consortium. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007; 130 (Pt 3): 843-852
• 51 Heron SE, Crossland KM, Andermann E. et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 2002; 360 (9336): 851-852
• 52 Vanoye CG, Gurnett CA, Holland KD, George Jr AL, Kearney JA. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 2014; 62: 313-322
• 53 Trudeau MM, Dalton JC, Day JW, Ranum LP, Meisler MH. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet 2006; 43 (06) 527-530
• 54 Hu H, Eggers K, Chen W. et al. ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet 2011; 89 (03) 407-414
• 55 Simpson MA, Cross H, Proukakis C. et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 2004; 36 (11) 1225-1229
• 56 Nikali K, Saharinen J, Peltonen L. cDNA cloning, expression profile and genomic structure of a novel human transcript on chromosome 10q24, and its analyses as a candidate gene for infantile onset spinocerebellar ataxia. Gene 2002; 299 (1-2): 111-115
• 57 Jacob FD, Ho ES, Martinez-Ojeda M, Darras BT, Khwaja OS. Case of infantile onset spinocerebellar ataxia type 5. J Child Neurol 2013; 28 (10) 1292-1295
• 58 Saitsu H, Kato M, Mizuguchi T. et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 2008; 40 (06) 782-788
• 59 Ostergaard E, Christensen E, Kristensen E. et al. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet 2007; 81 (02) 383-387
• 60 Casey JP, McGettigan P, Lynam-Lennon N. et al. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Mol Genet Metab 2012; 106 (03) 351-358
• 61 Basel-Vanagaite L, Hershkovitz T, Heyman E. et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet 2013; 93 (03) 524-529
• 62 Sun Y, Almomani R, Breedveld GJ. et al. Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum Mutat 2013; 34 (05) 706-713
• 63 Kanduc D. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity. Biol Chem 2019; 400 (05) 629-638
• 64 Choudhry H, Bakhrebah MA, Abdulaal WH. et al. Middle East respiratory syndrome: pathogenesis and therapeutic developments. Future Virol 2019; 14 (04) 237-246
• 65 Su S, Wong G, Shi W. et al. Epidemiology, genetic recombination, and pathogenesis of Coronaviruses. Trends Microbiol 2016; 24 (06) 490-502
• 66 Francis T, Salk JE, Quilligan JJ. Experience with vaccination against influenza in the spring of 1947: a preliminary report. Am J Public Health Nations Health 1947; 37 (08) 1013-1016
• 67 Lucchese G, Kanduc D. The Guillain–Barrè peptide signatures: from Zika virus to Campylobacter, and beyond. Virus Adapt Treat 2017; 9: 1-11
• 68 Lucchese G, Kanduc D. Minimal immune determinants connect Zika virus, human cytomegalovirus, and Toxoplasma gondii to microcephaly-related human proteins. Am J Reprod Immunol 2017; 77 (02) e12608
• 69 Kanduc D. Anti-SARS-CoV-2 immune response and sudden death: Titin as a link. Adv Stud Biol 2021; 13: 37-44
• 70 Kanduc D. Thromboses and hemostasis disorders associated with COVID-19: the possible causal role of cross-reactivity and immunological imprinting. Glob Med Genet 2021; 8 (04) 162-170
• 71 Davenport FM, Hennessy AV, Francis Jr T. Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J Exp Med 1953; 98 (06) 641-656
• 72 Fevang B, Wyller VBB, Mollnes TE. et al. Lasting immunological imprint of primary Epstein-Barr virus infection with associations to chronic low-grade inflammation and fatigue. Front Immunol 2021; 12: 715102