TY  - JOUR
AU  - Klaassen, Kristel
AU  - Đorđević, M.
AU  - Skakić, Anita
AU  - Kecman, B.
AU  - Drmanac, R.
AU  - Pavlović, Sonja
AU  - Stojiljković, Maja
PY  - 2021
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1466
AB  - Phenylketonuria (PKU) is an inborn error of metabolism caused by variants in the phenylalanine hydroxylase (PAH) gene and it is characterized by excessively high levels of phenylalanine in body fluids. PKU is a paradigm for a genetic disease that can be treated and majority of developed countries have a population-based newborn screening. Thus, the combination of early diagnosis and immediate initiation of treatment has resulted in normal intelligence for treated PKU patients. Although PKU is a monogenic disease, decades of research and clinical practice have shown that the correlation between the genotype and corresponding phenotype is not simple at all. Attempts have been made to discover modifier genes for PKU cognitive phenotype but without any success so far. We conducted whole genome sequencing of 4 subjects from unrelated non-consanguineous families who presented with pathogenic mutations in the PAH gene, high blood phenylalanine concentrations and near-normal cognitive development despite no treatment. We used cross sample analysis to select genes common for more than one patient. Thus, the SHANK gene family emerged as the only relevant gene family with variants detected in 3 of 4 analyzed patients. We detected two novel variants, p.Pro1591Ala in SHANK1 and p.Asp18Asn in SHANK2, as well as SHANK2:p.Gly46Ser, SHANK2:p.Pro1388_Phe1389insLeuPro and SHANK3:p.Pro1716Thr variants that were previously described. Computational analysis indicated that the identified variants do not abolish the function of SHANK proteins. However, changes in posttranslational modifications of SHANK proteins could influence functioning of the glutamatergic synapses, cytoskeleton regulation and contribute to maintaining optimal synaptic density and number of dendritic spines. Our findings are linking SHANK gene family and brain plasticity in PKU for the first time. We hypothesize that variant SHANK proteins maintain optimal synaptic density and number of dendritic spines under high concentrations of phenylalanine and could have protective modifying effect on cognitive development of PKU patients.
PB  - Elsevier, Amsterdam
T2  - Molecular Genetics and Metabolism Reports
T1  - Untreated PKU patients without intellectual disability: SHANK gene family as a candidate modifier
VL  - 29
DO  - 10.1016/j.ymgmr.2021.100822
ER  - 

@article{
author = "Klaassen, Kristel and Đorđević, M. and Skakić, Anita and Kecman, B. and Drmanac, R. and Pavlović, Sonja and Stojiljković, Maja",
year = "2021",
abstract = "Phenylketonuria (PKU) is an inborn error of metabolism caused by variants in the phenylalanine hydroxylase (PAH) gene and it is characterized by excessively high levels of phenylalanine in body fluids. PKU is a paradigm for a genetic disease that can be treated and majority of developed countries have a population-based newborn screening. Thus, the combination of early diagnosis and immediate initiation of treatment has resulted in normal intelligence for treated PKU patients. Although PKU is a monogenic disease, decades of research and clinical practice have shown that the correlation between the genotype and corresponding phenotype is not simple at all. Attempts have been made to discover modifier genes for PKU cognitive phenotype but without any success so far. We conducted whole genome sequencing of 4 subjects from unrelated non-consanguineous families who presented with pathogenic mutations in the PAH gene, high blood phenylalanine concentrations and near-normal cognitive development despite no treatment. We used cross sample analysis to select genes common for more than one patient. Thus, the SHANK gene family emerged as the only relevant gene family with variants detected in 3 of 4 analyzed patients. We detected two novel variants, p.Pro1591Ala in SHANK1 and p.Asp18Asn in SHANK2, as well as SHANK2:p.Gly46Ser, SHANK2:p.Pro1388_Phe1389insLeuPro and SHANK3:p.Pro1716Thr variants that were previously described. Computational analysis indicated that the identified variants do not abolish the function of SHANK proteins. However, changes in posttranslational modifications of SHANK proteins could influence functioning of the glutamatergic synapses, cytoskeleton regulation and contribute to maintaining optimal synaptic density and number of dendritic spines. Our findings are linking SHANK gene family and brain plasticity in PKU for the first time. We hypothesize that variant SHANK proteins maintain optimal synaptic density and number of dendritic spines under high concentrations of phenylalanine and could have protective modifying effect on cognitive development of PKU patients.",
publisher = "Elsevier, Amsterdam",
journal = "Molecular Genetics and Metabolism Reports",
title = "Untreated PKU patients without intellectual disability: SHANK gene family as a candidate modifier",
volume = "29",
doi = "10.1016/j.ymgmr.2021.100822"
}

Klaassen, K., Đorđević, M., Skakić, A., Kecman, B., Drmanac, R., Pavlović, S.,& Stojiljković, M.. (2021). Untreated PKU patients without intellectual disability: SHANK gene family as a candidate modifier. in Molecular Genetics and Metabolism Reports
Elsevier, Amsterdam., 29.
https://doi.org/10.1016/j.ymgmr.2021.100822

Klaassen K, Đorđević M, Skakić A, Kecman B, Drmanac R, Pavlović S, Stojiljković M. Untreated PKU patients without intellectual disability: SHANK gene family as a candidate modifier. in Molecular Genetics and Metabolism Reports. 2021;29.
doi:10.1016/j.ymgmr.2021.100822 .

Klaassen, Kristel, Đorđević, M., Skakić, Anita, Kecman, B., Drmanac, R., Pavlović, Sonja, Stojiljković, Maja, "Untreated PKU patients without intellectual disability: SHANK gene family as a candidate modifier" in Molecular Genetics and Metabolism Reports, 29 (2021),
https://doi.org/10.1016/j.ymgmr.2021.100822 . .

TY  - JOUR
AU  - Paunesku, T.
AU  - Stevanović, Milena
AU  - Radosavljević, D.
AU  - Drmanac, R.
AU  - Crkvenjakov, R.
PY  - 1990
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/73
AB  - We have reported in rat three adult β-gene haplotypes containing either five or three genes. Detailed sequence analysis reveals that the leftmost gene is the major gene and that at the opposite end downstream lies the minor gene. All of the genes lying between them are minor-major hybrids indicating their origin by unequal crossing-over. In two haplotypes β-globin genes were found with an L1 element inserted directly into IVS2. The described results allow the formulation of a pathway of mutational events leading from the ancient two-β-gene rodent ancestor through a three-gene haplotype to five-gene haplotypes, one of which is postulated to have arisen in common laboratory strains since their capture in the wild.
T2  - Molecular Biology and Evolution
T1  - Origin of rat β-globin haplotypes containing three and five genes
EP  - 422
IS  - 5
SP  - 407
VL  - 7
DO  - 10.1093/oxfordjournals.molbev.a040616
Abstract
ER  - 

@article{
author = "Paunesku, T. and Stevanović, Milena and Radosavljević, D. and Drmanac, R. and Crkvenjakov, R.",
year = "1990",
abstract = "We have reported in rat three adult β-gene haplotypes containing either five or three genes. Detailed sequence analysis reveals that the leftmost gene is the major gene and that at the opposite end downstream lies the minor gene. All of the genes lying between them are minor-major hybrids indicating their origin by unequal crossing-over. In two haplotypes β-globin genes were found with an L1 element inserted directly into IVS2. The described results allow the formulation of a pathway of mutational events leading from the ancient two-β-gene rodent ancestor through a three-gene haplotype to five-gene haplotypes, one of which is postulated to have arisen in common laboratory strains since their capture in the wild.",
journal = "Molecular Biology and Evolution",
title = "Origin of rat β-globin haplotypes containing three and five genes",
pages = "422-407",
number = "5",
volume = "7",
doi = "10.1093/oxfordjournals.molbev.a040616
Abstract"
}

Paunesku, T., Stevanović, M., Radosavljević, D., Drmanac, R.,& Crkvenjakov, R.. (1990). Origin of rat β-globin haplotypes containing three and five genes. in Molecular Biology and Evolution, 7(5), 407-422.
https://doi.org/10.1093/oxfordjournals.molbev.a040616
Abstract

Paunesku T, Stevanović M, Radosavljević D, Drmanac R, Crkvenjakov R. Origin of rat β-globin haplotypes containing three and five genes. in Molecular Biology and Evolution. 1990;7(5):407-422.
doi:10.1093/oxfordjournals.molbev.a040616
Abstract .

Paunesku, T., Stevanović, Milena, Radosavljević, D., Drmanac, R., Crkvenjakov, R., "Origin of rat β-globin haplotypes containing three and five genes" in Molecular Biology and Evolution, 7, no. 5 (1990):407-422,
https://doi.org/10.1093/oxfordjournals.molbev.a040616
Abstract . .

TY  - JOUR
AU  - Stevanović, Milena
AU  - Paunesku, T.
AU  - Radosavljević, D.
AU  - Drmanac, R.
AU  - Crkvenjakov, R.
PY  - 1989
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/69
AB  - The genomic organization of three haplotypes of β-globin genes was determined to resolve the question of the number of those genes in rat. Haplotype a, found in inbred strain DA, has three genes or pseudogenes, while haplotypes b, found in AO, Y5 and Wistar strains, and c, found in Wistar strain, have five genes or pseudogenes each. In haplotypes b and c, the first gene is of βmajor type and the remaining four are of βminir type. Partial sequencing of six out of 13 genes shows that duplications of βminor genes are causing polymorphism in a number of genes. Also, in haplotype b two βminor genes have a 6.5-kb intron 2, while in haplotype c only one βminor gene contains such a large intron 2. The three structurally different haplotypes described are not interconvertible by single recombination events. The results indicate that the rat has the highest number of adult β-globin genes found in mammals so far.
T2  - Gene
T1  - Variant chromosomal arrangement of adult β-globin genes in rat
EP  - 150
IS  - 1
SP  - 139
VL  - 79
DO  - 10.1016/0378-1119(89)90099-1
ER  - 

@article{
author = "Stevanović, Milena and Paunesku, T. and Radosavljević, D. and Drmanac, R. and Crkvenjakov, R.",
year = "1989",
abstract = "The genomic organization of three haplotypes of β-globin genes was determined to resolve the question of the number of those genes in rat. Haplotype a, found in inbred strain DA, has three genes or pseudogenes, while haplotypes b, found in AO, Y5 and Wistar strains, and c, found in Wistar strain, have five genes or pseudogenes each. In haplotypes b and c, the first gene is of βmajor type and the remaining four are of βminir type. Partial sequencing of six out of 13 genes shows that duplications of βminor genes are causing polymorphism in a number of genes. Also, in haplotype b two βminor genes have a 6.5-kb intron 2, while in haplotype c only one βminor gene contains such a large intron 2. The three structurally different haplotypes described are not interconvertible by single recombination events. The results indicate that the rat has the highest number of adult β-globin genes found in mammals so far.",
journal = "Gene",
title = "Variant chromosomal arrangement of adult β-globin genes in rat",
pages = "150-139",
number = "1",
volume = "79",
doi = "10.1016/0378-1119(89)90099-1"
}

Stevanović, M., Paunesku, T., Radosavljević, D., Drmanac, R.,& Crkvenjakov, R.. (1989). Variant chromosomal arrangement of adult β-globin genes in rat. in Gene, 79(1), 139-150.
https://doi.org/10.1016/0378-1119(89)90099-1

Stevanović M, Paunesku T, Radosavljević D, Drmanac R, Crkvenjakov R. Variant chromosomal arrangement of adult β-globin genes in rat. in Gene. 1989;79(1):139-150.
doi:10.1016/0378-1119(89)90099-1 .

Stevanović, Milena, Paunesku, T., Radosavljević, D., Drmanac, R., Crkvenjakov, R., "Variant chromosomal arrangement of adult β-globin genes in rat" in Gene, 79, no. 1 (1989):139-150,
https://doi.org/10.1016/0378-1119(89)90099-1 . .