Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні
Проаналізовано мутації Arg124Cys (екзон 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (екзон 12), His626Arg (екзон 14) гена TGFBI з використанням методу полімеразної ланцюгової реакції з наступною рестрикцією у 91 пацієнта з різними формами дистрофії рогівки та 31 клінічно здорового індивіда з 49 не...
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| Published in: | Біополімери і клітина |
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| Date: | 2008 |
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Інститут молекулярної біології і генетики НАН України
2008
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| Journal Title: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Cite this: | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні / В.М. Пампуха, Г.І. Дрожжина, Л.А. Лівшиць // Біополімери і клітина. — 2008. — Т. 24, № 1. — С. 60-68. — Бібліогр.: 52 назв. — укр., англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1860026678419390464 |
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| author | Пампуха, В.М. Дрожжина, Г.І. Лівшиць, Л.А. |
| author_facet | Пампуха, В.М. Дрожжина, Г.І. Лівшиць, Л.А. |
| citation_txt | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні / В.М. Пампуха, Г.І. Дрожжина, Л.А. Лівшиць // Біополімери і клітина. — 2008. — Т. 24, № 1. — С. 60-68. — Бібліогр.: 52 назв. — укр., англ. |
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| description | Проаналізовано мутації Arg124Cys (екзон 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (екзон 12), His626Arg (екзон 14) гена TGFBI з використанням методу полімеразної ланцюгової реакції з наступною рестрикцією у 91 пацієнта з різними формами дистрофії рогівки та 31 клінічно здорового індивіда з 49 неспоріднених родин. Отримані результати показують, що аналіз мутацій в гені TGFBI має важливе значення у диференційній діагностиці дистрофій рогівки з прогностичним і терапевтичним застосуванням, а також для генетичного консультування в родинах високого ризику.
In our study Arg124Cys (exon 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (exon 12), His626Arg (exon 14) mutations of the TGFBI gene were analyzed using polymerase chain reaction followed by restriction digestion in 91 patients with different forms of corneal dystrophy and 31 clinically healthy individuals from 49 unrelated families. Our results show that TGFBI gene mutations analysis is important for differential diagnostics of corneal dystrophies with prognostic and therapeutic implications as well as for genetic consulting in high risk families.
Проанализированы мутации Arg124Cys (экзон 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (экзон 12), His626Arg (экзон 14) гена TGFBI с использованием метода полимеразной цепной реакции с последующей рестрикцией у 91 пациента с разными формами дистрофии роговицы и среди 31 клинически здорового индивида из 49 неродственных семей. Полученные результаты свидетельствуют о том, что анализ мутаций в гене TGFBI имеет важное значение в дифференциальной диагностике дистрофий роговицы с прогностическим и терапевтическим применением, а также для генетического консультирования в семьях высокого риска.
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BIOMEDICINE
Study of TGFBI gene mutations in Ukrainian patients
with corneal dystrophies
V.M. Pampukha, G.I. Drozhyna1, L.A. Livshits
Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine
150, Zabolotny Str., Kyiv, 03680, Ukraine
1The V.P. Filatov institute of eye diseases and tissue therary of Academy of Medical sciences of Ukraine
49/51,Frantcuzkiy Bulvar, Odessa, 65061, Ukraine
livshits@imbg.org.ua
In this study Arg124Cys (exon 4), Thr538Arg, Ala546Thr, Arg555Thr, ARg55Gln (exon 12), His626Arg
(exon 14) mutations of the TGFBI gene were analyzed using polymerase chain reaction followed by
restriction digestion in 91 patients with different forms of corneal dystrophy and 31 clinically healthy
individuals from 49 unrelated families. Our results show that TGFBI gene mutations analysis is important
for differential diagnostics of corneal dystrophies with prognostic and therapeutic implications as well as
for genetic consulting in high risk families.
Keywords: TGFBI gene, keratoepithelin, corneal dystrophy
Introduction. TGFBI gene, or BIG-H3 (transforming
growth factor-beta induced gene) was discovered in
1992 by Skonier et al. while studying the influence of
transforming growth factor-beta on the cell lines of
human adenocarcinoma [1]. Two years later
independent investigations in two laboratories revealed
tgfbi protein in cornea as well [2, 3]. In the same year
three kinds of dystrophy of corneal stroma, namely,
lattice dystrophy (type I), granular dystrophy (type I),
and Avellino dystrophy were mapped on chromosome
5 [4]. Finally, in 1997 Munier et al. determined that
four types of dystrophy of corneal stroma (three
aforementioned plus Reis-Bucklers’ dystrophy) were
caused by different mutations in TGFBI gene [5]. This
gene was found to locate on the long arm of
chromosome 5 (5q31) and to encode extracellular
matrix protein, consisting of 683 amino acid residues.
Munier et al. called this protein “keratoepithelin”
because they believed it was expressed in cornea
solely. However, tgfbi protein was found also in other
tissues of the organism [1, 6]. Its carboxylic end
contains Arg-Gly-Asp sequence (RGD-motive), which
is recognized by surface receptor proteins – integrins
[7, 8]. Different investigations revealed covalent bond
between tgfbi protein and collagen VI in many tissues,
60
ISSN 0233-7657. Biopolymers and cell. 2008. vol. 24. N 1. Translated from Ukrainian
Ó V.M. PAMPUKHA, G.I. DROZHYNA, L.A. LIVSHITS, 2008
including cornea [9, 10], besides, it interacts with
fibronectin [11]. Tertiary structure of tgfbi protein is
similar to that of fasciclin I – protein, performing
adhesive function in nervous cells of insects [12].
Aforementioned proteins belong to a large family,
which is specific for the presence of tandem-repeated
homologous sequences, so called FAS1-domains.
Tgfbi protein consists of four such domains [13].
Hereditary corneal dystrophies are a
heterogeneous group of progressing diseases,
resulting in corneal opacities and significant loss of
vision. Dystrophies of corneal stroma, caused by
mutations in TGFBI gene, are autosomal dominant
diseases, characterised by a common feature – the
presence of abnormal deposits, localized either in
keratocytes or among collagen fibrils [14]. Lattice
dystrophy is specific for amyloid deposits, granular
dystrophy is characterised by hyaline deposits, while
Avellino dystrophy is notable for both amyloid and
hyaline deposits [15].
Most patients with corneal dystrophy have
mutations in codons 124 and 555 of TGFBI gene.
Besides, genetic investigations showed correlation
between some types of TGFBI mutations and clinical
forms of dystrophy, caused by them [5, 16–18].For
instance, mutation Arg124Cys is specific for lattice
dystrophy (type I), mutation Arg124His – for Avellino
dystrophy, mutation Arg124Leu – for Reis-Bucklers’
dystrophy, mutation Arg555Trp – for granular
dystrophy (type I), Arg555Gln – for Thiel-Behnke
dystrophy. The study on the relations of genotype and
phenotype revealed that homozygosity for mutations
in TGFBI gene causes more early onset and more
complicated clinical course [19, 20].
Lattice dystrophy is the most widely spread kind
of dystrophy, which as a rule is a bilateral
amyloidosis, characterized by refractive lattice lines.
Mutations in TGFBI gene cause several types of
lattice dystrophy. Lattice dystrophy (type I) is a
bilateral symmetrical disease of cornea,
characterized by numerous semi-transparent thin
lattice lines, associated with white spots in surface
and middle layers of central stroma. It was
established that symptoms appeared in 1st-2nd decade
of life. Patients with this form of disease often suffer
from relapses of erosive processes [21-23]. It was
shown that most patients with this type of disease
have mutation Arg124Cys, however, this phenotype
may be associated with other mutations, including
Leu518Arg, Leu569Arg, and Val539Asp [24–26].
In 1991 Stock et al. described a type of dystrophy,
specific for late onset and thick lattice formations
[27]. In this case corneal erosions are an inconstant
sign. This type of dystrophy is defined as lattice
dystrophy (type IIIA), associated with mutations
Pro501Thr (spread among Japanese), Ala546Thr (
among French), Asn622Lys, ASN622His ( the
population of the British Isles) [28–30]. In 1999 the
authors of [31] identified mutation His626Arg of
TGFBI gene in patients with late onset of lattice
dystrophy. In this case the dynamics of clinical
onsets in both eyes was asynchronic, i.e.
asymmetrical. Schmitt-Bernard et al. studied
clinical, histological, and ultrastructural specificities
of dystrophy, caused by this mutation, and came to
the conclusion that this type of dystrophy is a
separate group of lattice dystrophies – intermediary
between types I and IIIA, characterized by a more
early onset (3rd–4th decade of life) and thinner
lattice-like lines compared to type IIIA [32].
Fujiki et al. described so called deep form of
lattice dystrophy and distinguished it as the 4th type.
Its first clinical manifistation is shown in the 5th life
decade. They are characterized by deposits of
star-like form, located in deep layers of stroma.
Radial lattice-like structures in middle layers of
stroma occur later, while in the higher layers of
stroma and epithelium deposits are completely
absent. Different authors showed this type to be
associated with mutations Leu527Arg (notable for
Japanese), Val631Asp (specific for Italian), and
Gly594Val (found in India) [26, 30, 33].
Other autosomal dominant diseases, caused by
mutations in TGFBI gene, are granular corneal
dystrophies [23, 34]. Clinical picture of classical
granular dystrophy (type I, or Groenouw I), is
notable for grey-white non-transparent knots,
resembling bread crumbs, in corneal stroma. The first
disease signs are revealed in the 1st–2nd life decade.
With age their number and size increase, in some
places they merge and spread into middle and deep
layers of stroma [35, 36]. Some patients have erosive
61
STUDY OF TGFBI GENE MUTATIONS IN PATIENTS WITH CORNEAL DYSTROPHIES
processes in cornea and pain syndrome [37]. The
majority of patients with granular dystrophy (type I)
are found to have mutation Arg555Trp [5]. Mutation
Arg124Ser was discovered only in two families with
this type of dystrophy [38]. In case of Avellino
dystrophy manifestation of clinical signs starts in the
1st–3rd life decades. In young age abnormal
formations in cornea of patients with Avellino
dystrophy are in the form of circles, disks,
snowflakes, stars, located in front and middle layers
of stroma. Lattice-like formations appear later, they
are localized in the middle and deep layers of stroma
[39, 40]. All the patients with this type of dystrophy
are found to have only one mutation – Arg124His [5].
Reis-Bucklers’ dystrophy is also called dystrophy
of Bowman’s layer, type I. Disease symptoms,
including relapsing erosion and expressed pain
syndrome, start in the first life decade. Light
microscopy allows observing degeneration of basal
epithelium and Bowman’s layer, which are
completely or partially substituted by connective
tissue. Hyaline deposits, located under epithelium,
destroy Bowman’s layer. Electronic microscopy
reveals dense rod-like granules, ultrastructural
characteristics of which correspond to granular
dystrophy of corneal stroma [41, 42].
At present three mutations, namely, Arg124Leu,
deltaF540, and Gly623Asp, are known to be
associated with Reis-Bucklers’ dystrophy [43–45].
Light microscopy of cornea of patients with
Thiel-Behnke dystrophy allows observing clinical
picture, similar to Reis-Bucklers’ dystrophy. It is
noteworthy that both kinds of dystrophy affect the
same corneal layer and differ only in morphology .
In case of Thiel-Behnke dystrophy subepithelial
deposits enter epithelium in the form of numerous
wedges, resembling saw teeth. Electronic
microscopy shows curly filaments [46, 47]. Only
one mutation Arg555Gln of TGFBI gene is
associated with Thiel-Behnke dystrophy, however,
this type of dystrophy may be caused by mutations
in another gene, mapped on chromosome 10
(10q23-q24) [5, 48].
More than 30 mutations are identified in TGFBI
gene. The majority of them are located in exons 4, 12,
and 14. Investigations on the association of certain
mutant variants and clinical characteristics of corneal
dystrophy are important for both determination of the
function of tgfbi protein, and the analysis of
mechanisms of disease pathogenesis. In its turn, the
results of such investigations allow to improve
differential diagnostics and prognosis of clinical
course.
The aim of our work was to study mutations
Arg124Cys (exon 4), Thr538Arg, Ala546Thr,
Arg555Thr, Arg555Gln (exon 12), and His626Arg
(exon 14) of TGFBI gene in patients with different
clinical forms of corneal dystrophy.
Materials and Methods. Clinical and
molecular-genetic investigations were performed
with 91 patients with hereditary dystrophy of
corneal stroma from 49 families, and with 31
clinically healthy family members of patients. The
investigated group included 45 patients and 11
healthy persons from 20 families with lattice
dystrophy (type I), 16 patients and 1 healthy person
from 10 families with granular dystrophy (type I), 4
patients from 2 families with the clinical diagnosis
of Reis-Bucklers’ dystrophy, 26 patients and 18
healthy persons from 17 families with lattice
dystrophy and late onset.
The materials for molecular-genetic
investigation were samples of peripheral blood,
obtained at the conditions of informed consent of the
individuals from the investigated group. The
materials for morphological and histochemical
investigation were corneal disks, obtained after
performed keratoplasty. Histochemical and
ultrastructural analyses were conducted as described
in [49].
DNA preparations were extracted from
leukocytes of peripheral blood and purified by the
standard method of phenol-chloroform extraction
[50].
To analyse mutant variants of TGFBI gene we
conducted specific in vitro amplification of
DNA-sequences of exons 4, 12, and 14 by the
method of polymerase chain reaction (PCR) [51] in
automatic regime on Perkin Elmer thermocycler
(Cetus, USA) according to the following scheme:
denaturation of DNA – 45 sec, 94°C; annealing of
primers – 45 sec, 55°C; elongation – 1 min, 72°C.
62
PAMPUKHA V.M., DROZHYNA G.I., LIVSHITS L.A.
Specific oligonucleotides, synthesized in
accordance to corresponding exon sequences of
TGFBI gene, were used as primers:
for mutation Arg124Cys –
forward (5 -CAGAGGCCATCCCTCCTTCT-3 ),
reverse (5 -CAGGCCTCAGCTTCTCCCTG-3 );
for mutations Thr538Arg, Ala546Thr, Arg555Thr –
forward (5 -GGACTGACGGAGACCCTCAA-3 ),
reverse (5 -GGAGACGTGTACTTAAGTTGGTC-3 );
for mutation Arg555Gln –
forward (5 -GGACTGACGGAGACCCTCAA-3 ),
reverse (5 -CTTTACCCAAGAGTCAGATC-3 );
for mutation Hys626Arg –
forward (5 -GAAAAACAATGTGGTGAGTGTC-3 ),
reverse (5 -CATGGAGAAAAGGACTGGCTG-3 ).
To perform differential analysis of some types of
mutations, amplified sequences of exons 4, 12, and 14
were hydrolyzed by restriction endonucleases PstI,
HinfI, MwoI, BstXI, BglII, NlaIII for mutations
Arg124Cys, Thr538Arg, Ala546Thr, ARg555Thr,
ARg555Gln, Hys626Arg, respectively.
Results and Discussion. Molecular-genetic
analysis of exon 12 of TGFBI gene revealed mutation
Arg555Thr in five families with clinical diagnosis of
granular corneal dystrophy, including the case of a
9-year-old child (Fig.1). Other five families with
clinical diagnosis of granular dystrophy did not have
mutation R555W, specific for this dystrophy kind.
Detailed study of clinical picture in four families
showed clinical signs, notable for macular corneal
dystrophy. Besides, it is possible to forecast autosomal
recessive type of inheritance in these families.
Therefore, the analysis of genealogy and phenotypic
signs of disease with the consideration of the data of
molecular-genetic analysis allowed reviewing the
primary diagnosis.
Clinical and genealogic analysis of all the patients
with lattice dystrophy demonstrated the autosomal
dominant type of inheritance. Histochemical
investigations were performed on the material of cornea
after keratoplasty. Patients with clinical diagnosis of
lattice corneal dystrophy showed morphological and
ultrastructural features, specific for this kind of
dystrophy [49].
63
STUDY OF TGFBI GENE MUTATIONS IN PATIENTS WITH CORNEAL DYSTROPHIES
Fig.1 Analysis of mutation R555W in exon 12 of TGFBI gene in patients
with granular dystrophy (PCR + BstXI; 10% PAAG): 1 – marker of
molecular weight pUC19DNA/MspI; 2, 3 – patients; 4 – healthy
individuals
Fig.2 Analysis of mutation R124C in exon 4 of TGFBI gene in patients
with lattice corneal dystrophy (PCR + PstI; 10% PAAG): 1, 2 – healthy
individuals; 3, 4, 5 – patients; 6 – marker of molecular weight
pUC19DNA/MspI
Molecular-genetic analysis of exon 4 of TGFBI
gene allowed determining mutation Arg124Cys in
patients of 15 families and one 11-year-old child, who
did not have clinical signs of lattice dystrophy, type I
(Fig.2). Besides, this mutation was found in a patient
with clinical diagnosis of Reis-Bucklers’ dystrophy.
Since mutation Arg124Cys causes the development of
lattice dystrophy (type I), the primary diagnosis of this
patient was reviewed. Five families with clinical
diagnosis of lattice dystrophy (type I) did not have
mutation Arg124Cys. Another family with the primary
clinical diagnosis of Reis-Bucklers’ dystrophy had
mutation Arg555Gln, associated with Thiel-Behnke
dystrophy (Fig.3). The primary clinical diagnosis of
this family was also changed. Similarity of clinical
pictures for Thiel-Behnke dystrophy and
Reis-Bucklers’ dystrophy, as well as similar early
onsets of these kinds of dystrophy and lattice dystrophy
are reasons of wrong diagnoses.
We did not identify mutation Ala546Thr using
molecular-genetic analysis in any investigated patients
with late onset of corneal dystrophy. It was found only
in French patients [29].
The investigations performed determined mutation
Hys626ARg in patients from 12 families; only in one
family with primary clinical diagnosis of lattice
dystrophy (type IIIA) this mutation was not revealed
(Fig.4). Besides, the mutation was found in six persons
who did not have clinical signs of disease yet. It is
worth mentioning that mutation Hys626Arg was also
found in one patient with the clinical diagnosis of lattice
dystrophy (type I) which afforded grounds for doubting
the sufficiency of data of clinical investigation to define
correct diagnosis and identify the form of the disease.
This assumption is also favoured by the results of the
analysis of mutation Thr538ARg in the investigated
group of patients. This mutation was not found in any
patients with late onset of lattice dystrophy. However,
mutation Thr538Arg was found in a patient with
clinical diagnosis of lattice dystrophy, type I (Fig.5).
Munier et al. supposed that mentioned mutation,
discovered by Othenin-Girard et al, similar to mutation
Hys626Arg, may be associated with the intermediary,
type I/IIIA [30, 52]. It is interesting that patients from
four families with mutation Hys626Arg were
characterized by so called asymmetry of clinical
picture. It was evident from the fact that pathological
deposits were observed in one eye first, and only in
64
PAMPUKHA V.M., DROZHYNA G.I., LIVSHITS L.A.
Fig.3 Analysis of mutation R555Q in exon 4 of TGFBI gene (PCR +
BglII; 10% PAAG): 1 – marker of molecular weight pUC19DNA/MspI;
2, 3 – heterozygous mutation carriers; 4 – healthy individual
Fig.4 Analysis of mutation H626R in exon 14 of TGFBI gene in patients
with lattice corneal dystrophy (PCR + NlaIII; 10% PAAG): 1 – marker
of molecular weight GeneRuler 50bp DNA Ladder; 2, 3, 4 – patients; 5,
6 – healthy individuals
several years slight manifestations of lattice dystrophy
may be found in the other eye. At present nobody
suggests a possible mechanism of these processes,
therefore, detailed study of the structure and features of
mutant protein and its interaction with protein-partners
may clarify the nature of the asymmetry phenomenon.
Four of investigated families had characteristic
symptoms of lattice dystrophy (type IV). None of them
had mutations.
Clout and Hohenester believe that hot spots for
mutations in positions Arg124 and Arg555 are
located in the sequence, encoding the binding site of
á-spirals in protein domains 1 and 4, and
substitutions of these amino acid residues destroy
stability and solubility of the protein rather than its
structure [13]. Mutations Arg124His and Arg124Cys
cause the formation of amyloid deposits, but other
mutations in positions Arg124 and Arg555 make the
protein more hydrophobic and thus lead to the
formation of hyaline deposits. On the other hand,
some researchers believe that most mutations,
located in the 4th Fas1-domain, have more significant
influence on the protein structure, since they are
located in conservative positions. However, this
assumption does not explain insignificant
destruction of the protein structure by mutations in
other three homologous domain of tgfbi.
The results of modelling the tertiary structure of
domain 4 of tgfbi protein allowed assuming that
mutation Thr538Arg, resulting in the substitution of
threonine for arginine, causes the disorder in folding of
protein product, which, in its turn, makes protein
secretion impossible [13]. The authors of this work
consider that amyloid deposits in patients with this
mutation should appear in the first life decade.
However, we revealed mutation Thr538Arg in a
patient, whose disease manifestation appeared in the
third life decade.
Basing on the results of modelling, we came to the
conclusion that protein secretion becomes impossible
when mutation Ala546Thr occurs, because this
mutation results in its significant destabilization.
Mutation His626Arg destroys hydrogen bonds.
Besides, conservatism of histidine in this position,
observed in domains of all proteins of
Fas1-superfamily, testifies to its significance for the
process of folding, therefore, it is not likely that the
protein with mutation His626Arg will be folded and
secreted. Taking into consideration forecasted
functions of mutant proteins, determined by the results
of modelling tertiary structure, it is possible to assume
that patients with mutations Thr538Arg and His626Arg
will have early onset. However, the data obtained by us,
do not support such assumption. All our patients with
mentioned mutations, except for one case with the
primary clinical diagnosis of lattice dystrophy, type I,
and early onset, had the beginning of disease
manifestation in the 3rd-4th life decade.
The accumulation of mutant protein tgfbi in the
form on insoluble deposits takes place only in cornea,
though this protein is expressed in other tissues as well,
therefore, it is possible to assume that tissue-specific
factors are involved in pathogenesis. It is yet to be
discovered why mutations in one gene or even
mutations in one codon are capable of inducing such
different phenotypic manifestations. For instance, in
case of substituting arginine in codon 124 for cysteine,
leucine, histidine, the deposits of amyloid, hyaline or
mixed deposits are formed in cornea.
Previously the diagnosis of different forms of
hereditary corneal dystrophy was made on the basis of
specific clinical picture as well as typical
morphological and histochemical features. Taking into
65
STUDY OF TGFBI GENE MUTATIONS IN PATIENTS WITH CORNEAL DYSTROPHIES
Fig.5 Analysis of mutation T538R in exon 12 of TGFBI gene in patients
with lattice corneal dystrophy (PCR + HinfI; 10% PAAG): 1, 2 –
patients; 3, 4, 5 – healthy individuals; 6 – marker of molecular weight
pUC19DNA/MspI
account that morphological and histochemical
investigations using the material of cornea are possible
only after keratoplasty, the main role in setting the
diagnosis in pre-surgery period is given to the clinical
picture of disease.
Molecular-genetic analysis of mutations in TGFBI
gene is highly informative for the purpose of accurate
differential diagnostics of hereditary dystrophy of
corneal stroma, it is also very important for performing
pre-symptomatic diagnostics in the members of patient
family and forecasting the clinical course with
corresponding therapy.
The obtained data on the association of mutant
variants of TGFBI gene and clinical signs of dystrophy
of corneal stroma give reasonable grounds for
conclusion that the efforts in understanding
pathogenesis of this disease should be directed onto the
determination of the nature of interaction of
tissue-specific factors and mutant protein tgfbi in
cornea, as well as onto the clarification of factors,
influencing its structure and stability.
Â. Ì. Ïàì ïó õà, Ã. ². Äðîæ æè íà, Ë. À. ˳âøèöü
Äîñë³äæåí íÿ ìó òàö³é ãåíà TGFBI
ó õâî ðèõ íà äèñ òðîô³þ ñòðî ìè ðîã³âêè,
ÿê³ ïðî æè âà þòü â Óêðà¿í³
Ðå çþ ìå
Ïðî à íàë³çî âà íî ìó òàö³¿ Arg124Cys (åê çîí 4), Thr538Arg,
Ala546Thr, Arg555Thr, Arg55Gln (åê çîí 12), His626Arg (åê çîí
14) ãåíà TGFBI ç âè êî ðèñ òàí íÿì ìå òî äó ïîë³ìå ðàç íî¿ ëàí öþ ãî -
âî¿ ðå àêö³¿ ç íà ñòóï íîþ ðåñ òðèêö³ºþ ó 91 ïàö³ºíòà ç ð³çíè ìè
ôîð ìà ìè äèñ òðîô³¿ ðîã³âêè òà 31 êë³í³÷íî çäî ðî âî ãî ³íäèâ³äà ç
49 íå ñïîð³äíå íèõ ðî äèí. Îòðè ìàí³ ðå çóëü òà òè ïî êà çó þòü, ùî
àíàë³ç ìó òàö³é â ãåí³ TGFBI ìຠâàæ ëè âå çíà ÷åí íÿ ó äè ôå -
ðåíö³éí³é ä³àã íîñ òèö³ äèñ òðîô³é ðîã³âêè ç ïðî ãíîñ òè÷ íèì ³
òå ðà ïåâ òè÷ íèì çà ñòî ñó âàí íÿì, à òà êîæ äëÿ ãå íå òè÷ íî ãî êîí -
ñóëü òó âàí íÿ â ðî äè íàõ âè ñî êî ãî ðè çè êó.
Êëþ ÷îâ³ ñëî âà: ãåí TGFBI, êå ðà òî åï³òåë³í, äèñ òðîô³ÿ
ðîã³âêè.
Â. Í. Ïàì ïó õà, Ã. È. Äðîæ æè íà, Ë. À. Ëèâ øèö
Èññëå äî âà íèå ìó òà öèé ãåíà TGFBI ó áîëü íûõ ñ äèñ òðî ôè ÿ ìè
ñòðî ìû ðî ãî âè öû, ïðî æè âà þ ùèõ â Óêðàèíå
Ðå çþ ìå
Ïðî à íà ëè çè ðî âà íû ìó òà öèè Arg124Cys (ýê çîí 4), Thr538Arg,
Ala546Thr, Arg555Thr, Arg55Gln (ýê çîí 12), His626Arg (ýê çîí
14) ãåíà TGFBI ñ èñ ïîëü çî âà íè åì ìå òî äà ïî ëè ìå ðàç íîé öåï íîé
ðå àê öèè ñ ïî ñëå äó þ ùåé ðåñ òðèê öè åé ó 91 ïà öè åí òà ñ ðàç íû ìè
ôîð ìà ìè äèñ òðî ôèè ðî ãî âè öû è ñðå äè 31 êëè íè ÷åñ êè
çäî ðî âî ãî èí äè âè äà èç 49 íå ðî äñòâåí íûõ ñå ìåé. Ïî ëó ÷åí íûå
ðå çóëü òà òû ñâè äå ò åëüñòâó þò î òîì, ÷òî àíà ëèç ìó òà öèé â
ãåíå TGFBI èìå åò âàæ íîå çíà ÷å íèå â äèô ôå ðåí öè àëü íîé äè àã -
íîñ òè êå äèñ òðî ôèé ðî ãî âè öû ñ ïðî ãíîñ òè ÷åñ êèì è òå ðà ïåâ -
òè ÷åñ êèì ïðèìåíåíèåì, à òàêæå äëÿ ãåíåòè÷åñêîãî
êîíñóëüòèðîâàíèÿ â ñåìüÿõ âûñîêîãî ðèñêà.
Êëþ ÷å âèå ñëî âà: ãåí TGFBI, êå ðà òî ý ïè òå ëèí, äèñ òðî ôèÿ
ðî ãî âè öû
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UDC 575.11:577.21:576.31:617.713-007.17-02
Received 04.06.07
68
PAMPUKHA V.M., DROZHYNA G.I., LIVSHITS L.A.
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| id | nasplib_isofts_kiev_ua-123456789-157664 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0233-7657 |
| language | English |
| last_indexed | 2025-12-07T16:50:04Z |
| publishDate | 2008 |
| publisher | Інститут молекулярної біології і генетики НАН України |
| record_format | dspace |
| spelling | Пампуха, В.М. Дрожжина, Г.І. Лівшиць, Л.А. 2019-06-20T16:18:30Z 2019-06-20T16:18:30Z 2008 Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні / В.М. Пампуха, Г.І. Дрожжина, Л.А. Лівшиць // Біополімери і клітина. — 2008. — Т. 24, № 1. — С. 60-68. — Бібліогр.: 52 назв. — укр., англ. 0233-7657 https://nasplib.isofts.kiev.ua/handle/123456789/157664 575.11:577.21:576.31:617.713-007.17-02 Проаналізовано мутації Arg124Cys (екзон 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (екзон 12), His626Arg (екзон 14) гена TGFBI з використанням методу полімеразної ланцюгової реакції з наступною рестрикцією у 91 пацієнта з різними формами дистрофії рогівки та 31 клінічно здорового індивіда з 49 неспоріднених родин. Отримані результати показують, що аналіз мутацій в гені TGFBI має важливе значення у диференційній діагностиці дистрофій рогівки з прогностичним і терапевтичним застосуванням, а також для генетичного консультування в родинах високого ризику. In our study Arg124Cys (exon 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (exon 12), His626Arg (exon 14) mutations of the TGFBI gene were analyzed using polymerase chain reaction followed by restriction digestion in 91 patients with different forms of corneal dystrophy and 31 clinically healthy individuals from 49 unrelated families. Our results show that TGFBI gene mutations analysis is important for differential diagnostics of corneal dystrophies with prognostic and therapeutic implications as well as for genetic consulting in high risk families. Проанализированы мутации Arg124Cys (экзон 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (экзон 12), His626Arg (экзон 14) гена TGFBI с использованием метода полимеразной цепной реакции с последующей рестрикцией у 91 пациента с разными формами дистрофии роговицы и среди 31 клинически здорового индивида из 49 неродственных семей. Полученные результаты свидетельствуют о том, что анализ мутаций в гене TGFBI имеет важное значение в дифференциальной диагностике дистрофий роговицы с прогностическим и терапевтическим применением, а также для генетического консультирования в семьях высокого риска. en Інститут молекулярної біології і генетики НАН України Біополімери і клітина Біомедицина Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні Исследование мутаций гена TGFBI у больных с дистрофиями стромы роговицы, проживающих в Украине Study of TGFBI gene mutations in Ukrainian patients with corneal dystrophies Article published earlier |
| spellingShingle | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні Пампуха, В.М. Дрожжина, Г.І. Лівшиць, Л.А. Біомедицина |
| title | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні |
| title_alt | Исследование мутаций гена TGFBI у больных с дистрофиями стромы роговицы, проживающих в Украине Study of TGFBI gene mutations in Ukrainian patients with corneal dystrophies |
| title_full | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні |
| title_fullStr | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні |
| title_full_unstemmed | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні |
| title_short | Дослідження мутацій гена TGFBI у хворих на дистрофію строми рогівки, які проживають в Україні |
| title_sort | дослідження мутацій гена tgfbi у хворих на дистрофію строми рогівки, які проживають в україні |
| topic | Біомедицина |
| topic_facet | Біомедицина |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/157664 |
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