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 »  Abstract
 »  Introduction
 »  Case report
 »  Material and methods
 »  Results
 »  Discussion
 »  Acknowledgements
 »  References

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Year : 2001  |  Volume : 49  |  Issue : 1  |  Page : 19-24

Deficiency of the 50 kDa dystrophin-associated-glycoprotein (adhalin) in an Indian autosomal recessive limb girdle muscular dystrophy patient : immunochemical analysis and clinical aspects.


Human Molecular Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

Correspondence Address:
Human Molecular Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

  »  Abstract

Abnormalities of dystrophin are a common cause of muscular dystrophy and testing for dystrophin gene or protein has become a part of routine diagnostic evaluation of patients who present with progressive proximal muscle weakness, high serum creatine kinase concentrations, and histopathological evidence of a dystrophic process. Patients who have no dystrophin abnormalities are assumed to have autosomal recessive muscular dystrophy. In a family consisting of 5 sibs, 2 mentally normal brothers presented with abnormal gait and protrusion of chest and hips. Muscle biopsy from one of them showed dystrophic changes and reduced patchy binding of dystrophin. No detectable deletion was observed in the patient's DNA and his brother with cDMD probes. Dystrophin associated proteins, beta-dystroglycan showed discontinuous immunostaining in the sarcolemma and alpha-sarcoglycan (adhalin) was totally absent, while beta-, gamma-, and delta-sarcoglycans were highly reduced. Immunoblot analysis showed dystrophin of normal molecular weight but of decreased quantity, beta-dystroglycan was reduced by about 37% while alpha-sarcoglycan was completely absent. This study is a first attempt for a systematic clinical, genetic and molecular investigation of the autosomal recessive LGMD in India.

How to cite this article:
Handa V, Mital A, Gupta M, Goyle S. Deficiency of the 50 kDa dystrophin-associated-glycoprotein (adhalin) in an Indian autosomal recessive limb girdle muscular dystrophy patient : immunochemical analysis and clinical aspects. Neurol India 2001;49:19-24


How to cite this URL:
Handa V, Mital A, Gupta M, Goyle S. Deficiency of the 50 kDa dystrophin-associated-glycoprotein (adhalin) in an Indian autosomal recessive limb girdle muscular dystrophy patient : immunochemical analysis and clinical aspects. Neurol India [serial online] 2001 [cited 2020 Jan 29];49:19-24. Available from: http://www.neurologyindia.com/text.asp?2001/49/1/19/1307




   »   Introduction Top

Autosomal recessive limb girdle muscular dystrophies
(AR-LGMD) are a heterogenous group of genetic
disorders in which there is a progressive weakness of
the pelvic and shoulder girdle musculature. Eight
genes have already been mapped for AR-LGMDs
which are : LGMD2A at 15q, LGMD2B at 2p,
LGMD2C at 13q, LGMD2D at 17q, LGMD2E at 4q,
LGMD2F at 5q, LGMD2G at 17q and LGMD2H at
9q.[1],[2],[3],[4],[5],[6],[7],[8],[9] Among these AR-LGMDs : LGMD2D,
LGMD2E, LGMD2C and LGMD2F arise from
mutations in genes encoding four different
dystrophin-associated glycoproteins [DAG /
dystrophin-associated proteins (DAP)], -(adhalin),
-, - and -sarcoglycans respectively.[3],[4],[5],[6],[7],[10],[11],[12] In
1992, Matsumura et al[13] reported adhalin deficiency
in patients presenting with severe childhood
autosomal recessive muscular dystrophy (SCARMD)
from Algeria and Lebanan. The clinical phenotype of
this disease was close to Duchenne (DMD) and
Becker (BMD) muscular dystrophies as reported
earlier by Ben-Hamida et al.[14] Presence of dystrophin
in muscle biopsy specimens led to a search for
deficiency in one of the DAPs (adhalin).[13],[14],[15] Several
authors have subsequently reported adhalin deficiency
in European, Brazilian and Asian patients with
SCARMD or milder muscular dystrophies.[16],[17],[18],[19],[20],[21],[22],[23]
Genetic studies indicated a heterogeneity of adhalin
deficiencies. Ben-Othmane et al[24] mapped the
defective gene, responsible for the form of the
SCARMD prevalent in north Africa, to chromosome
13q12 and this was confirmed by Azibi et al.[25]
Roberds et al26 mapped the adhalin gene to
chromosome 17q12-q21.[33] and identified the first
missense mutations in a previously reported French
family.[4],[26] Different groups subsequently reported
other cases of 'primary adhalinopathy'.[20],[22],[27]
Piccolo et al[27] described 12 biochemical deficient -
sarcoglycan families and showed -sarcoglycan gene
mutations in 9 of them while in a molecular screen of
30 north American muscular dystrophy patients with
normal dystrophin, a single African-American girl
with -sarcoglycan gene mutation and a phenotype
consistent with childhood-onset muscular dystrophy
was identified.28 The frequency of -sarcoglycan
deficiency in Japanese patients has been studied using
immunohistochemical data. However, the primary
gene defect was not known and these patients may
include secondary adhalin deficiency.[23] Secondary
adhalin deficiencies are due to mutations affecting -,
- and -sarcoglycan genes.[3],[5],[6],[12]
We report here one Indian patient whose intellectual
development was normal and there was no heart
dysfunction. A complete absence of 50 DAG, partial
deficiency of dystrophin and -dystroglycan, and
variable reactivity with merosin was observed. This
case illustrates the potential risk of misdiagnosis in
patients exhibiting a patchy pattern of dystrophin.

   »   Case report Top

We studied one family whose two affected siblings
(BJ and BJB) born of nonconsanguineous marriage
were non ambulant at the time of presentation. They
had similar phenotypes with normal developmental
milestones. They had two younger brothers and one
sister in good health. The sibs BJ and BJB, 16 and 14
year old males; mentally normal, presented with
progressive difficulty in walking and frequent falls for
the last 5 years. The trunk, arms and legs of both the
probands were globally thin. On examination, there
was proximal muscle weakness of the upper limbs
with limited range of movements in all joints. The
hip, knee, and the ankle joints were fixed due to
contractures. Deep tendon reflexes were ellicitable in
the upper limbs but not in lower limbs due to
contractures. ECG was normal. EMG examination
showed low voltage, short amplitude, polyphasic
action potentials. Serum creatine kinase (CK) was
elevated to 1680 U/L (BJ) and 4881 U/L (BJB).

   »   Material and methods Top

DNA Analysis : Peripheral blood samples were
obtained from BJ and BJB and unrelated healthy
control subject. Genomic DNA was digested with
restriction endonuclease Hind III and separated by
electrophoresis through 1.2% agarose gel, 20-24cm in
length and transferred to hybond N+ membrane
(Amersham,UK) by Southern blotting technique with
some modifications.29 cDMD probes 1-2a, 2b-3, 4-5a,
5b-7, 8 and 9-14 were obtained from ATCC, USA.
Probe 9-14 was further digested with BamHI to
separate probes 9, 10 and 11-14. DNA analysis was
also carried out by mPCR using three different
multiplex primer sets comprising 9 primer pairs each
(IMMCO Corporation, USA). The PCR products were
separated on 2.5% agarose gels. Multiplex I (exons ;
45, 48, 19, 17, 51, 8, 12, 44, 4) and Multiplex II
(exons; Pm, 3, 43, 50, 13, 6, 47, 60, 52) were designed
by Chamberlain et al30 and Beggs et al respectively.31
Multiplex III (exons: 49, 16, 41, 32, 42, 2,79, 25, 66)
was designed in our laboratory based on the sequences
by Beggs (personal communication). No other family
member agreed to undergo a blood test for
determination of CK and DNA analysis.
Immunocytochemistry : Skeletal muscle biopsy was
obtained from the gastrocnemius muscle of the patient
BJ. Muscle biopsy was snap frozen in liquid nitrogen.
The cryostat sections were processed for
immunocytochemistry with indirect immunoperoxidase
technique.32 Frozen muscle sections, 6 m
thick were incubated with monoclonal antibodies
against dystrophin (N-terminal, rod domain and Cterminal),
-dystroglycan, -, -, - and -
sarcoglycans and laminin- 2 (Novacastra, Newcastle,
UK). These antibodies were used at dilution shown in
[Table I]. Incubation with primary antibodies was
performed for 1 hr, followed by an incubation with
1:50 diluted peroxidase labelled goat anti mouse Ig
20
(Novacastra, Newcastle, UK), with TBS; (0.05 M
TrisHCI pH 7.6) for 1 hour at room temperature. Each
incubation step was followed by extensive washing
with TBS. Visualisation was achieved by exposure to
freshly prepared 0.05% (w/v) diaminobenzidiene in
TBS containing 0.1% hydrogen peroxide. Muscle
sections were examined under Leitz Orthoplan,
microscope. Negative controls were always included.
Western Blot : Western blotting was carried out using
thick SDS-polyacrylamide gel with discontinuous
system modified by the use of 0.2% (w/v) of SDS
throughout.33,34 The separated proteins were blotted
onto PVDF membrane (Amresco, USA) using transfer
buffer of Otter et al at 400 mA overnight.35
Immunoreaction was performed using monoclonal
antibodies against dystrophin (rod-domain, Cterminal),
-dystroglycan and -sarcoglycan. These
antibodies were used at dilution shown in [Table I].
Visualisation was achieved using chemiluminescence
working solution (Pierce, USA).
Quantification of dystrophin and its associated
proteins : The quantity (relative cellular abundance) of
dystrophin, -dystroglycan and -sarcoglycan was
also determined as a percentage of the adjacent
normal control samples. This approximation was
completely dependent on the amount of muscle tissue
loaded in each lane, determined by post-transfer
myosin stain.[36]

   »   Results Top

DNA Analysis
The restriction pattern observed in patient's DNA
sample and his brother with dystrophin cDNA probes
completely matched that of a control DNA sample,
indicating that no structural alteration such as deletion
or duplication were present in the dystrophin gene.
Immunocytochemistry (Dystrophin and Spectrin)
Immuno-cytochemistry of dystrophin : Patchy
labelling with reduced intensity was seen with the
antibody against N-terminal domain, but the pattern
was more severe against the rod-domain which also
revealed more negative fibres. Staining with Cterminal
domain antibody also showed patchy
labelling but with reduced intensity as compared to Nterminal.
Spectrin immunostaining in the muscle
fibres was almost identical to that of dystrophin. The
staining was patchy and the intensity was slightly less
than that seen with N-terminal domain of dystrophin.
Very few negative fibres were observed.
Dystrophin associated proteins and Laminin- 2 :
Immunostainability of -dystroglycan antibody in the
muscle was moderately reduced as compared to
normal controls. In contrast, staining for -
sarcoglycan was completely absent, while -, - and
-sarcoglycans were highly reduced in the
sarcolemma of the muscle fibres [Figure - 1]. A reduction
in the intensity of immunostaining for laminin- 2
around each muscle fibre was seen [Figure - 2].
Immunoblot analysis
Dystrophin and Dystrophin associated proteins
[Figure - 3]: Immunoblot analysis of muscle proteins
showed dystrophin of normal molecular weight (427
kDa), but of decreased quantities by densitometric
analysis. On being compared to normal control,
presence of 90% and 89% of dystrophin was observed
with antibodies against mid-rod and carboxyl
terminal, respectively. Presence of 63% of -
dystroglycan was observed, while no immunoreactivity
was seen with - sarcoglycan.

   »   Discussion Top

Sarcoglycanopathies are muscular dystrophies due to
disruption of the dystrophin-associated sarcoglycan
complex caused by mutations in any of the four
already identified sarcoglycan genes ( -, -, - and -
SG).[3],[4],[5],[6],[7] Mutations in any one of these sarcoglycans
lead to more or less pronounced secondary
deficiencies of the other components of the complex,
indicating the importance of the integrity of the entire
complex for the prevention of muscle cell
degeneration.37 The clinical severity of primary -
sarcoglycanopathy varies strikingly. The most severe
course has been observed in whom -SG was
completely absent. A pronounced but variable
decrease in -SG, were usually observed in milder
forms of variable severity.[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38] The characteristic of
the affected members of this family are: (i) the
peculiar clinical presentation in being able to slide on
their buttocks; (ii) with late onset but rapid
progression resulting in contractures of hip, knee and
ankle joints.
In agreement with Beckmann and Bushby, to
discriminate between different LGMD2 entities, both
immunocytochemistry and western blot are helpful
for the initial screening.[39] -SG immunocytochemistry
can be taken as the first step to screen
all the cases for sarcoglycanopathy and to separate
these cases from others. Mutations of any component
of the sarcoglycan complex result in the secondary
loss of the other components of the complex. In many
cases, the defective sarcoglycan protein was not
detected by immunocytochemical analysis, whereas
other sarcoglycans were weakly or strongly stained.40
In patients with -sarcoglycan deficiency on
immunostaining, a complete deficiency (absence of
staining) was found to be more specific for mutations
in the -sarcoglycan gene than for mutations in - or
-sarcoglycan gene. On the other hand, a partial
deficiency of -sarcoglycan on immunostaining was
not specific for mutations in any of the three
sarcoglycan gene. It is most likely that patient BJ
suffered from primary adhalinopathy, since
immunoreactivity for -sarcoglycan was completely
absent while -, - and -sarcoglycans were highly
reduced.
Immunocytochemistry revealed a patchy pattern with
antibodies against dystrophin in BJ while slightly
reduced amount of dystrophin was observed (90% of
normal with rod-domain and 89% of the normal with
C-terminal domain) in western blot. Normal amount
of dystrophin has been observed in SCARMD.[15],[16],[27]
In contrast, studies by Duggan et al[41] in LGMD2D
patients showed reduced to variable staining with
antibodies directed against dystrophin while muscle
protein studies by Passos-Bueno et al[42] in Brazilian
population for seven autosomal recessive LGMDs
revealed that dystrophin was reduced in quantity in all
LGMD2C, 2E, and 2F patients. However, among the
seven LGMD2D only one patient who was severely
affected showed a reduction in dystrophin quantity by
western blot. Staining for -dystroglycan in BJ was
found to be patchy while by immunoblot a moderate
reduction of -dystroglycan (63% of the normal) was
observed. Duggan et al[41] reported one patient with
partial deficiency of -sarcoglycan who also showed
variable staining with -dystroglycan out of 30 cases
of childhood muscular dystrophy. -dystroglycan was
found to be preserved in SCARMD patients from
north-Africa, Europe and Japan.[13],[16],[23]
In conclusions, our results suggest that the severity of
the clinical course in patient BJ correlated with the
total absence of adhalin and that the stability of
dystrophin in the myofibre plasma membrane is
somewhat dependent upon -sarcoglycan.

   »   Acknowledgements Top

A Fellowship to VH from University Grants
Commission, and financial help from Department of
Biotechnology and Indian Council of Medical
Research, New Delhi is gratefully acknowledged.
 

  »   References Top

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41.progressive muscular dystrophy. Curr Opin Neurol 1997; 9 :389-393.  Back to cited text no. 41    
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43.Duggan DJ, Fanin M, Pegoraro E et al : ?-sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal musclar dystrophy and most partial deficeincy patients donot have gene mutations. J Neurol Sci1996; 140 : 30-39.  Back to cited text no. 43    
44.Passos-Bueno MR, Vainzof M, Moreira ES et al : Seven autosomal recessive limb-girdle muscular dystrophies in Brazilian population : From LGMD2A to LGMD2C. Am J Hum Genet1999; 82 : 392-398.  Back to cited text no. 44    

 

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