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Exploration of gene variations in the transcytosis system as a policy proposal for the personalized therapy in type 2 diabetes mellitus

Luis J. Flores-Alvarado

Biochemistry Laboratory, Health Sciences University Center, Universidad de Guadalajara, Mexico

José R. Villafán-Bernal

CONACYT Cathedratic at Division of Surgery, Universidad Autónoma de Aguascalientes, Mexico

Carlos E. Cabrera-Pivaral

Research Center for Social Development, Health Sciences University Center, Universidad de Guadalajara, Mexico

Carlos J. Castro-Juárez

Institute of Public Health Research,Universidad de la Sierra Sur, Oaxaca, Mexico

Sergio A. Ramirez-Garcia

Institute of Public Health Research,Universidad de la Sierra Sur, Oaxaca, Mexico

DOI: 10.15761/JMT.1000108

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Abstract

The gene system of transcytosis, integrated by LRP2, AMN, CUBN, ARH, AMN and CUBN, might be important for the treatment and monitoring of chronic complications of diabetics, as well as for drug interactions, since they mediate the reuptake of vitamins such as B complex, folic acid and lipoproteins, which are closely related to the progression of diabetes. That is why polymorphisms in those genes could be targets of personalized medicine, to improve the quality of health care.

Key words

 cubilin, diabetes, hypercholesterolemia, megalin

It is important for both the clinical researcher and physician to explore new personalized treatment options for better care of the diabetic patient. The search for genetic or genomic markers in order to predict complications of disease, progression as well as to evaluate the therapeutic response to drugs and the presentation of adverse effects is an area to be explored, considering the high costs that represent the attention of diabetics to hospitals from the public sector. Other reasons are that type 2 diabetes mellitus (T2D) patients develop complications related with the progression of the disease, as well as, adverse and side effects resulting from drug interactions [1,2].

T2D commonly presents deficiency of vitamin B complex, associated with the long-term consumption of metformin. The consequences of this deficiency are increased cardiovascular risk, renal damage and higher risk of peripheral neuropathy and senile dementia [1,2]. Additionally, the chronic consumption of statins for the control of hypercholesterolemia and cardiovascular risk results in secondary dyslipidemia myocytes inflammation [1,2].

The common element that might explain the previously described complications and side effects in T2D diabetic patients is an axis of genes that encode for the system of transcytosis in the cellular membranes from small intestine, kidney, liver, striated muscle, and other tissues. The components of this transcytosis system are LRP2, AMN, CUBN, ARH, Dab2, GIPC, NHE3, ClC5, FcRn and NaPi-IIa, which mediate the reuptake of B complex vitamins, including folic acid among other molecules [3-10].

The clinical effect of these genes might be seen in the development of different diseases or clinical conditions (Table 1). Mutations in LRP2 have been associated with diabetes, aminoglucosides response, Donnai-Barrow syndrome (DBS), Facio-oculo-acoustic-renal syndrome (FOAR) and Alzheimer's disease. While mutations in AMN and CUB occur with megaloblastic anemia plus albuminuria. CUBallelic variants are related to the progression of renal damage and ARH variations are associated with hypercholesterolemia [3-10]. NHE3 mutations show association with congenital sodium diarrhea, whereas ClC5 gene is related to renal failure or Dent disease. ClC5, FcRn, NaPi-IIa gene are related with metabolic renal disease. DAB2, GIPC has an uncertain meaning in human pathology, but their pathogenic effect must be explored [11-25].

 

Gene

Protein

SNP or pathogenicmutation

Reference

LRP2

Megalin

rs133980 (associated with hypertension),

rs2544390 (associated with gout and alcohol drinking)

rs1050700 (associated with glomerular filtration rate)

rs3755166, rs2075252, rs4668123 (associated with central adiposity),

rs2075252 and haplotype GA of rs4667591/ rs2075252 (associated with bone mineral density),

rs3755166 (associated with Alzheimer's disease

p.H498Q (associated with type 2 diabetes mellitus)

c.+193826T/C (associated with hypercholesterolemia)

[3-4]

CUB

Cubilin

rs1801239/p.I2984V(associated with diabetic nephropathy and albuminuria)

rs1801240/ p.G3002E (associated with diabetic nephropathy and albuminuria)

p.L2153F (associated with albuminuria)

p.I2984V (associated with diabetic nephropathy)

p.Q3002G (associated with diabetic nephropathy)

rs7918972 (associated with proteinuria)

[5,8]

AMN

Amnionless

c.35delA, p.Gln12Argfs*5 (associated Imerslund-Gräsbeck Syndrome)

c.206 T > A, p.Met69Lys 5 (associated Imerslund-Gräsbeck Syndrome)

p.Val2865Met 5 (associated Imerslund-Gräsbeck Syndrome)

c.363G>A , exon 5 (associated Imerslund-Gräsbeck Syndrome)

c.829A>G (T276A), c.1339_1344dup GCCGGG, c.-87C>G ,c.-87C>G , c.-27T>C, c.-23G>C, c.296-75_-66dup GCGTGGCGTG, c.843+11C>T, c.1169+42C>G, c.1170-6C>T, c.1362+38G>C, c.1362+518C>T, c.1362+523G>A (associated with recurrent spontaneous abortions).

14delG, 122C>T (recessive megaloblastic anemia)

[7,12,13]

ARH or LDLRAP1

Low density lipoprotein receptor adaptor protein 1

p.T56M, del 1.6kb exon 4  (recessive hypercholesterolemia).

p.P202S, p.P202H, p.R238Trp (determinants of plasma cholesterol levels)

[14-16]

DAB2

Clathrin adaptor protein

rs148700350,  rs200879578 , rs200879578, rs200754366            

Gene Bank, Not yet studied, Uncertain significance

GIPC

PDZ domain containing family member 1

rs770458112, rs764183065, rs369693566, rs373945556, rs775587781, rs770090326, rs752071186    

    

Gene Bank, Not yet studied, Uncertain significance

SLC9A3 or NHE3

Solute carrier family 9 member A3

c.1145G>A,  c.932C>T , c.[379G>A; 963_964delGT] , c.[379G>A; 963_964delGT] , c.805G>A , c.1446+1G>A , c.782dupG , c.1153G>A c.1145G>A, (congenital sodium diarrhea).

p.R474Q, p.V567M, p.R799C (decrease NHE3 transporter activity).

G1131A and C1197T (sudden infant death syndrome and sudden infant death syndrome)

[17-19]

CLCN5 o CLC5

Chloride voltage-gated channel 5

p.T657S, p.R345W and p.Q629X, insertion in codon 650 Alu (Dent disease)

[20-21]

FCGRT orFcRn

Fc fragment of IgG receptor and transporter

VNTR of promoter region (Response to cetuximab)

[22]

SLC34A1

 or NaPi-IIa

Solute carrier family 34 member 1

c.1484G>A, p.R95H (hypophosphatemia and nephrocalcinosis).

91del7, p.A133V and p.H568Y (calcium nephrolithiasis with renal phosphate leak).

p.R215W, p.C336G, p.V498E, p.W488R, IVS6(+1)G>A, IVS9(+3_6)del, IVS12(+1)G>A (associated with Idiopathic Infantile Hypercalcemia)

[23-25]

Table 1. Genotype of the of the endocytosis system

Considering the interaction between these genes, it would be very useful to analyze the relationship between polymorphisms of single base changes (SNP) of these genes, or the blocks of haplotypes and haplogroups that can be constructed with sets of SNP in T2D patients. Specially, the relationship of such variants with the development of peripheral neuropathy and the appropriate metformin doses. Another field of research is to explore the relationship between the response to statin therapy and the development of myocyte inflammation. The results of this genetic exploration might be translated into predictive markers to prevent complications associated with the commonly used drugs in T2D, allowing a better attention to the patient. These and other personalized medicine protocols should be included by many governments, since they would improve the costs of health care, especially since these genes are directly responsible for renal, neurological and vascular damage, as has been demonstrated in genetic diseases, animal and experimental models.

References

  1. Rosales RC, López JJ, Núñez NY, González AE, Ramirez-Garcia SA (2010) Type 2 diabetes nephropathy: a thresholds complex trait and chromosomal morbid map. Rev Med Inst Mex Seguro Social 48: 521-530. [Crossref]
  2. Ramirez-Garcia SA, Cabrera CE, Huacuja L, Flores LJ, Pérez G, et al. (2013) Implications in primary health care of medical genetics and genomic in type 2 diabetes mellitus. Rev Med Inst Mex Seguro Social 51: e6-e26. [Crossref]
  3. Ruiz P, Ramirez-Garcia SA, Cruz J, Cabrera EC (2014) Insights in the Postgenomic Era of the Folates, Vitamin B-12, Selenium and Public Policy in Health. Vitam Miner 3: 124.
  4. Carrillo C, González M, Ramirez-Garcia SA (2009) Detección molecular de una variante de secuencia del gen que codifica para megalina y el desarrollo de insuficiencia renal causada por diabetes mellitus tipo 2. Bioquimia 34: 59.
  5. Flores LJ, Ramirez-Garcia SA, Ferman PD, Daválos NO, Chavéz C, et al (2014) Molecular heterogeneity of type 2 diabetes mellitus in mexican population and its impact of the public health on policies in primary care. Med Chem 4: 791-790.
  6. 2021 Copyright OAT. All rights reserv
  7. Kur E1, Mecklenburg N, Cabrera RM, Willnow TE, Hammes A (2014) LRP2 mediates folate uptake in the developing neural tube. J Cell Sci 127: 2261-2268. [Crossref]
  8. Montgomery E, Sayer JA, Baines LA, Hynes AM, Vega V, et al (2015) Novel compound heterozygous mutations in AMN cause Imerslund-Gräsbeck syndrome in two half-sisters: a case report. BMC Med Genet 16: 35. [Crossref]
  9. Carrillo C, González M, Godínez S (2007) Detección molecular de variantes de secuencia del gen que codifica para cubilina y el desarrollo de insuficiencia renal causada por diabetes mellitus tipo 2. Bioquimia 32: 73.
  10. Reznichenko A, Snieder H, van den Born J, de Borst MH, Damman J, et al. (2012) CUBN as a novel locus for end-stage renal disease: insights from renal transplantation. PLoS One 7: e36512. [Crossref]
  11. De S, Kuwahara S, Saito A (2014) The Endocytic Receptor megalin and its associated proteins in proximal tubule epithelial cells. Membranes (Basel) 4: 333-355. [Crossref]
  12. Oliva- PF, Siqueiros JM, Vázquez JR, Saruwatari G, Carnevale A (2013) Genomic medicine in public health policies: a perspective of Mexican biomedical researchers. Salud Publica Mex 55: 16-25. [Crossref]
  13. Kaare M, Painter JN, Ulander VM, Kaaja R, Aittomäki K (2006) Variations of the Amnionless gene in recurrent spontaneous abortions. Mol Hum Reprod 12: 25-29. [Crossref]
  14. Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, et al. (2003) Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet 33: 426-429. [Crossref]
  15. Harada K, Miyamoto Y, Morisaki H, Ohta N, Yamanaka I, et al. (2010) A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia. J Atheroscler Thromb 17: 131-140. [Crossref]
  16. Quagliarini F, Vallvé JC, Campagna F, Alvaro A, Fuentes-Jimenez FJ, et al. (2007) Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene. Mol Genet Metab 92: 243-248. [Crossref]
  17. Hubacek JA, Hyatt T (2004) ARH missense polymorphisms and plasma cholesterol levels. Clin Chem Lab Med 42: 989-990. [Crossref]
  18. Janecke AR, Heinz-Erian P, Yin J, Petersen BS, Franke A, et al. (2015) Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum Mol Genet 24: 6614-6623. [Crossref]
  19. Zhu XC, Sarker R, Horton JR, Chakraborty M, Chen TE, et al (2015) Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity. Am J Physiol Cell Physiol 308: C758-766. [Crossref]
  20. Studer J, Bartsch C, Haas C (2014) Sodium/proton exchanger 3 (NHE3) and sudden infant death syndrome (SIDS). Int J Legal Med 128: 939-943. [Crossref]
  21. Tang X, Brown MR, Cogal AG, Gauvin D, Harris PC, et al. (2016) Functional and transport analyses of CLCN5 genetic changes identified in Dent disease patients. Physiol Rep 4: e12776. [Crossref]
  22. Claverie-Martin F, González-Acosta H, Flores C, Antón-Gamero M, García-Nieto V (2003) De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease. Hum Genet 113: 480-485. [Crossref]
  23. Passot C, Azzopardi N, Renault S, Baroukh N, Arnoult C, et al. (2013) Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies. MAbs 5: 614-619. [Crossref]
  24. Rajagopal A, Braslavsky D, Lu JT, Kleppe S, Clément F, et al. (2014) Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis. J Clin Endocrinol Metab 99: E2451-E2456. [Crossref]
  25. Lapointe JY, Tessier J, Paquette Y, Wallendorff B, Coady MJ, et al. (2006) NPT2a gene variation in calcium nephrolithiasis with renal phosphate leak. Kidney Int 69: 2261-2267. [Crossref]
  26. Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, et al. (2016) Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. J Am Soc Nephrol 27: 604-614. [Crossref]

Editorial Information

Editor-in-Chief

Article Type

Short Communication

Publication history

Received: February 28, 2017
Accepted: March 28, 2017
Published: March 31, 2017

Copyright

©2017 Flores-Alvarado LJ.. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Flores-Alvarado LJ, Villafán-Bernal JR, Cabrera-Pivaral CE, Castro-Juárez CJ, Ramirez-Garcia SA (2017) Exploration of gene variations in the transcytosis system as a policy proposal for the personalized therapy in type 2 diabetes mellitus. J Med Therap 1: DOI: 10.15761/JMT.1000108

Corresponding author

Sergio Alberto Ramirez-Garcia

Institute of Public Health Research, Universidad de la Sierra Sur. Oaxaca System of State Universities. Guillermo Rojas Mijangos S/N Ciudad Universitaria, Miahuatlán de Porfirio Diaz, Oaxaca, México

 

Gene

Protein

SNP or pathogenicmutation

Reference

LRP2

Megalin

rs133980 (associated with hypertension),

rs2544390 (associated with gout and alcohol drinking)

rs1050700 (associated with glomerular filtration rate)

rs3755166, rs2075252, rs4668123 (associated with central adiposity),

rs2075252 and haplotype GA of rs4667591/ rs2075252 (associated with bone mineral density),

rs3755166 (associated with Alzheimer's disease

p.H498Q (associated with type 2 diabetes mellitus)

c.+193826T/C (associated with hypercholesterolemia)

[3-4]

CUB

Cubilin

rs1801239/p.I2984V(associated with diabetic nephropathy and albuminuria)

rs1801240/ p.G3002E (associated with diabetic nephropathy and albuminuria)

p.L2153F (associated with albuminuria)

p.I2984V (associated with diabetic nephropathy)

p.Q3002G (associated with diabetic nephropathy)

rs7918972 (associated with proteinuria)

[5,8]

AMN

Amnionless

c.35delA, p.Gln12Argfs*5 (associated Imerslund-Gräsbeck Syndrome)

c.206 T > A, p.Met69Lys 5 (associated Imerslund-Gräsbeck Syndrome)

p.Val2865Met 5 (associated Imerslund-Gräsbeck Syndrome)

c.363G>A , exon 5 (associated Imerslund-Gräsbeck Syndrome)

c.829A>G (T276A), c.1339_1344dup GCCGGG, c.-87C>G ,c.-87C>G , c.-27T>C, c.-23G>C, c.296-75_-66dup GCGTGGCGTG, c.843+11C>T, c.1169+42C>G, c.1170-6C>T, c.1362+38G>C, c.1362+518C>T, c.1362+523G>A (associated with recurrent spontaneous abortions).

14delG, 122C>T (recessive megaloblastic anemia)

[7,12,13]

ARH or LDLRAP1

Low density lipoprotein receptor adaptor protein 1

p.T56M, del 1.6kb exon 4  (recessive hypercholesterolemia).

p.P202S, p.P202H, p.R238Trp (determinants of plasma cholesterol levels)

[14-16]

DAB2

Clathrin adaptor protein

rs148700350,  rs200879578 , rs200879578, rs200754366            

Gene Bank, Not yet studied, Uncertain significance

GIPC

PDZ domain containing family member 1

rs770458112, rs764183065, rs369693566, rs373945556, rs775587781, rs770090326, rs752071186    

    

Gene Bank, Not yet studied, Uncertain significance

SLC9A3 or NHE3

Solute carrier family 9 member A3

c.1145G>A,  c.932C>T , c.[379G>A; 963_964delGT] , c.[379G>A; 963_964delGT] , c.805G>A , c.1446+1G>A , c.782dupG , c.1153G>A c.1145G>A, (congenital sodium diarrhea).

p.R474Q, p.V567M, p.R799C (decrease NHE3 transporter activity).

G1131A and C1197T (sudden infant death syndrome and sudden infant death syndrome)

[17-19]

CLCN5 o CLC5

Chloride voltage-gated channel 5

p.T657S, p.R345W and p.Q629X, insertion in codon 650 Alu (Dent disease)

[20-21]

FCGRT orFcRn

Fc fragment of IgG receptor and transporter

VNTR of promoter region (Response to cetuximab)

[22]

SLC34A1

 or NaPi-IIa

Solute carrier family 34 member 1

c.1484G>A, p.R95H (hypophosphatemia and nephrocalcinosis).

91del7, p.A133V and p.H568Y (calcium nephrolithiasis with renal phosphate leak).

p.R215W, p.C336G, p.V498E, p.W488R, IVS6(+1)G>A, IVS9(+3_6)del, IVS12(+1)G>A (associated with Idiopathic Infantile Hypercalcemia)

[23-25]

Table 1. Genotype of the of the endocytosis system