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Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease) A genotype-phenotype correlation study.

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Molecular Heterogeneity of
Myophosphorylase Deficiency
(McArdle’s Disease): A Genotype–Phenotype
Correlation Study
Miguel A. Martı́n, Pharm B,1 Juan C. Rubio, MSc,1 Jenny Buchbinder, PhD,2 Roberto Fernández-Hojas, PhD,3
Pilar del Hoyo, Pharm B,1 Susana Teijeira, PhD,3 Josep Gámez, MD,4 Carmen Navarro, MD,3
José M. Fernández, MD,3 Ana Cabello, MD,1 Yolanda Campos, MSc,1 Carlos Cervera, MD,4
José M. Culebras, PhD,5 Antoni L. Andreu, PhD,4 Robert Fletterick, PhD,2 and Joaquı́n Arenas, PhD1
We report on 54 Spanish patients with McArdle’s disease from 40 unrelated families. Molecular analysis revealed that the
most common R49X mutation was present in 70% of patients and 55% of alleles. The G204S mutation was less frequent
and found in 14.8% of patients and 9% of mutant alleles. The W797R mutation was observed in 16.5% of patients,
accounting for 13.7% of mutant alleles. Moreover, 78% of mutant alleles among Spanish patients can be identified by
using polymerase chain reaction-restriction fragment length polymorphism analysis for the R49X, G204S, and W797R
mutations, which makes noninvasive diagnosis possible through molecular genetic analysis of blood DNA. Six novel
mutations were found. Three were missense mutations, E348K, R601W, and A703V; two nonsense mutations, E124X
and Q754X; and one single base pair deletion, 533 delA. No clear genotype–phenotype correlation emerges from our
study. Most of the mutations of uncharged and solvent inaccessible residues and the truncations must disrupt the basic
structure of the protein. The mutations of charged residues would be expected to interfere with internal hydrogen
bonding networks, introducing severe incompatible partnering that is caused by poor packing or electrostatic repulsions.
Ann Neurol 2001;50:574 –581
Glycogen phosphorylase (␣-1,4-glucan orthophosphate
glycosyltransferase, EC 2.4.1.1.) initiates glycogen
breakdown by removing ␣-1,4-glucosyl residues phosphorylytically from the outer branches of glycogen with
liberation of glucose-1-phosphate.1 The enzyme exists
as a homodimer containing two identical subunits of
97,000 Da each.2 Normal mature human muscle has a
single phosphorylase isozyme (MPL) whose gene has
been cloned, sequenced,3 and assigned to chromosome
11q13.4 Genetic defects of the myophosphorylase gene
(PYGM) cause a typical metabolic myopathy (McArdle’s
disease, MIM 232600), characterized by onset in the
second or third decade of life, exercise intolerance, premature fatigue, myalgia, cramps in exercising muscles,
and sometimes recurrent myoglobinuria.5–7 Brief efforts
involving isometric contraction and less intense but sustained dynamic exercise are the activities more likely to
cause symptoms.8 Most patients describe experiencing a
“second wind,” although many of them learn to adjust
their activities and can lead relatively normal lives.8
Molecular heterogeneity has been demonstrated by the
identification of various different mutations in the coding
regions or splice sites of the gene.9 –24 The most common
among European and US patients is a nonsense mutation
at codon 49 in exon 1 (R49X).9,11,15,25–28
We present molecular studies in 54 patients with
McArdle’s disease, describe six novel mutations in the
PYGM gene, and undertake to correlate clinical phenotype and genotype.
From the 1Centro de Investigación y Sección de Neuropatologı́a,
Hospital Universitario 12 de Octubre, Madrid, Spain; 2Department
of Biochemistry, Biophysics and Cellular and Molecular Pharmacology, University of California, San Francisco, CA; 3Departamento de
Neuropatologı́a y Neurofisiologı́a, Hospital do Meixoeiro, Vigo;
4
Centre d’Investigacions en Bioquı́mica i Biologia Molecular y Servicio de Neurologı́a, Hospitals Vall d⬘Hebron, Barcelona; and 5Departamento de Bioquı́mica y Biologı́a Molecular, Universidad Complutense de Madrid, Madrid, Spain.
Received Mar 20, 2001, and in revised form Jun 28. Accepted for
publication Jun 29, 2001.
574
© 2001 Wiley-Liss, Inc.
Patients and Methods
Patients
We studied 54 Spanish patients with McArdle’s disease (32
male and 22 female), ranging in age from 6 to 81 years, from
Published online Aug 28, 2001; DOI: 10.1002/ana.1225
Address correspondence to Dr Arenas, Centro de Investigación,
Hospital Universitario 12 de Octubre, Avenida de Andalucı́a km
5,4, 28041 Madrid, Spain. E-mail: [email protected]
40 unrelated families. In 34 patients, MPL deficiency was
documented both biochemically (undetectable levels of the
enzyme) and histochemically by a muscle biopsy, and in 8
patients it was confirmed histochemically alone. The other
12 patients were symptomatic relatives of patients with confirmed disease. This study was approved by the ethical committee of our institutions, and informed consent was obtained from human subjects.
The main clinical findings of the patients are shown in
Table 1. Forty-nine were adults and 5 were children (3 boys,
aged 8, 10, and 13 years; and 2 girls, aged 6 and 15 years).
The children aged 6 and 8 years had extremely mild symptoms consisting of tiredness and poor stamina, and their diagnosis was established because they had older affected siblings. The remaining patients presented with the typical
manifestations of the disease: exercise intolerance describing a “second wind,” muscle cramps, and myalgia. Acute
muscle necrosis and myoglobinuria occurred in 32 patients,
and 2 of them developed acute renal failure. Episodes of
myoglobinuria were usually followed by complete clinical recovery. Fixed weakness was seen in 14 patients, all of them
being older than 40 years. In all patients, resting serum CK
levels were increased (range, 300 –304,100IU/L; normal,
⬍150IU/L), and forearm ischemic exercise test revealed no
increase in venous lactate. Molecular analysis was performed
in muscle DNA in 42 patients and in blood DNA in 12
patients.
Control muscle samples consisted of biopsies obtained for
diagnostic purposes from individuals ultimately deemed to
be free of neuromuscular diseases. We analyzed control
genomic DNAs from muscle or blood of 60 normal individuals and 10 patients with various metabolic myopathies: 3
with myoclonic epilepsy and ragged-red fibers; 2 with mitochondrial encephalomyopathy, lactic acidosis, and strokelike
episodes; 1 with muscle phosphofructokinase deficiency; and
4 with muscle carnitine palmitoyltransferase II deficiency.
Genomic DNA Extraction and Screening for Two
Known Mutations
Genomic DNA was extracted from muscle or blood by standard methods, and screened for the mutations R49X and
G204S by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), as described elsewhere.11
Polymerase Chain Reaction Amplification of Genomic
DNA and Sequencing
The coding sequence of the entire PYGM gene (20 exons)
was amplified by PCR from genomic DNA in 14 fragments
with the primers described by Kubisch and colleagues.14 The
PCR products were purified by the GFX Gel Band Purification Kit (Amersham Pharmacia Biotech, Piscataway, NJ) and
sequenced with the ABIDyeDeoxy Terminator Cycle sequencing kit (Perkin-Elmer Applied Biosystems, Foster City,
CA) on an ABI Prism System 310 according to the manufacturer’s specifications. Sequences were compared with the
revised genomic structure of PYGM.14 To confirm the presence of novel mutations, we used PCR-RFLP analysis (Fig 1).
Results
In our patients with McArdle’s disease, screening by
PCR-RFLP showed that 21 patients were homozygous
for the R49X mutation and 2 for the G204S mutation.29 Five had compound heterozygotes for the R49X
and G204S mutations, 12 for the R49X mutation and
an unidentified mutant allele, and 1 for the G204S
mutation and an unidentified mutant allele. Three homozygous patients with the R49X mutation (Patients
10, 13, and 19) were reported in the paper by Andreu
and colleagues.26 Thirteen patients harbored neither
mutation in their alleles.
Sixteen further mutations were identified. Of them,
Table 1. Clinical Findings and Genotype-Phenotype Correlation in Patients with McArdle’s Disease
Phenotype
First Symptom (NP)
EI
Myalgia
plus EI
Cramps
(n)
Mb
(urine)
(n)
Fixed
Weakness
(n)
Genotype
NP
Age at Diagnosis
(yr)
Patients
Homozygous for nonsense or
frameshift mutations
R49X
Others
Homozygous for missense
mutations
W797R
G204S
Others
Compound heterozygous
54
23
37 ⫾ 18 (6–81)
36 ⫾ 20 (6–64)
16
7
14
6
24
10
50
22
32
15
14
5
21
2
10
36 ⫾ 20 (6–64)
(16–48)
46 ⫾ 18 (22–81)
6
1
3
6
0
3
9
1
4
20
2
8
14
1
6
5
0
4
6
2
2
21
53 ⫾ 18 (33–81)
(23–50)
(22–54)
33 ⫾ 13 (10–60)
2
1
0
6
3
0
0
5
1
1
2
10
5
2
1
20
3
2
1
11
3
1
0
5
Myalgia
Age ⫽ mean ⫾ standard deviation and/or range in parenthesis.
Mb ⫽ myoglobine; EI ⫽ exercise intolerance.
Martı́n et al: McArdle’s Disease
575
Fig 1. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP; top panels) and sequence analysis (bottompanels) of novel mutations in PYGM. (A) E124X mutation was analyzed with a forward primer 5⬘-TCA CTC CTC CAG CTG
GGC CTG GAC ATG GAG GAG CCT GA-3⬘ (mismatch underlined), 4r primer14 and SauI digestion; lane 1, 355 bp fragment
in the homozygous patient; lane 2, 320 and 35 bp fragments in a control. (B) E348K mutation was analyzed with the primers 9f
and 9r14 and AvaI digestion; lane 1, undigested 292 bp fragment; lane 2, 250, 158, 92, and 42 bp fragments in the compound
heterozygote patient; lane 3, 158, 92, and 42 bp fragments in a control. (C) 533 delA mutation was analyzed with the primers
13a and 13r14 and Msl I digestion; lane 1, undigested 263 bp fragment; lanes 2 and 3, 210, 112, 97, and 53 bp fragments in 2
compound heterozygote patients; lane 4, 250 and 53 bp fragments in a control. (D) R601W mutation was analyzed with the
primers 15a and 15r14 and StyI digestion; lane 1, 418, 320, 98, and 64 bp fragments in the compound heterozygote patient; lane
2, 418 and 64 bp fragments in a control. (E) A703V mutation was analyzed with 17f primer,14 a mismatched reverse primer
5⬘-CTC CAC CCG CAT GCC AAA GAT GAA GAA GTT TTC CTC TCG C-3⬘ (mismatch underlined) and HhaI digestion;
lane 1, 259 bp undigested PCR product; lane 2, 220 bp fragment in a control; lane 3, 259 and 220 bp fragments in the compound heterozygote patient. (F) Q754X mutation was analyzed with 18f primer,14 a mismatched reverse primer (5⬘-ATC TTG
ACA ATG TCC TTG AAC AGG TCG GGA T-3⬘ (mismatch underlined) and FokI digestion; lane 1, 219 bp undigested fragment; lane 2, 219 and 179 bp fragments in the compound heterozygote patient; lane 3, 179 bp fragment in a control. Fragments
sizes are on the left in each panel. Bottom of panels A–F, electropherograms showing the mutated bases at different positions (asterisks).
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10 have been reported elsewhere: 5⬘ivs14 g3a ,12 753
delA,14,15 L115P,19 N684Y,16 794/795 delAA,22
R193W,22 T487N,21 A659D,23 W797R,20,30 and 387
insA/del 8 bp.24 Patients with L115P, N684Y, 794/
795 delAA, R193W, T487N, A659D, and 387 insA/
del 8 bp mutations are identical to those in whom
these mutations have been first reported.16,19,21–24 Of
the 9 patients with the W797R mutation described
here, 4 have been documented in previous reports.20,30
Six novel mutations were found: three missense mutations, E348K, R601W, and A703V; two nonsense
mutations, E124X and Q754X; and one single base
pair deletion, 533 delA. DNA from 60 healthy individuals and 10 disease controls did not have any of
these mutations. The results of molecular analysis and
distribution of mutant alleles in the 54 patients with
McArdle’s disease are shown in Table 2.
When patients were classified according to their genotype, we observed no apparent correlation between
severity of clinical findings and presence of a particular
genotype (see Table 1).
Three Missense Mutations (E348K, R601W, and
A703V)
We identified three novel missense mutations in 3 patients who were heterozygous for the R49X mutation:
a heterozygous C-to-A substitution that changed CAG
(Glu) to AAG (Lys) at codon 348 (E348K) in exon 9;
a heterozygous C-to-T transition that changed CGG
Table 2. Mutations in the PYGM Gene in 54 Patients with
McArdle’s Disease
No.
Patients
Gender
(M/F)
21
5
3
2
2
1
1
1
1
1
2
1
6
1
1
11/10
3/2
3/0
1/1
1/1
0/1
0/1
0/1
0/1
1/0
2/0
1/0
4/2
1/0
1/0
1
2
1
1
a
Genotype
Allele 1
Allele 2
1/0
1/1
R49X
R49X
R49X
R49X
R49X
R49X
R49X
R49X
R49X
R49X
G204S
G204S
W797R
A659D
R193W and
794/795
delAA
E124Xa
753 delA
0/1
1/0
5⬘ivs14 g3a
L115P
R49X
G204S
W797R
T487N
533 delAa
A703Va
R601Wa
Q754Xa
E348Ka
753 delA
G204S
N684Y
W797R
A659D
R193W and
794/795
delAA
E124Xa
387 insA/del
8bp
5⬘ivs14 g3a
L115P
Novel mutations described in this study.
(Arg) to TGG (Trp) at codon 601 (R601W) in exon
15; and a heterozygous C-to-T transition that changed
GCG (Ala) to GTG (Val) at codon 703 (A703V) in
exon 17 (see Fig 1B, D, and E).
Two Nonsense Mutations (E124X, Q754X)
One patient was homozygous for a single base mutation, the substitution of G to T at codon 124 within
exon 3, changing an encoded glutamate (GAA) to a
stop codon TAA (E124X). In another patient, who was
heterozygous for the R49X mutation, we found a
C-to-T transition that changed CAG (Arg) to a stop
codon TAG (Q754X; see Fig 1A and F).
A Single Base Pair Deletion
In 2 siblings who were heterozygous for the R49X mutation, a novel single bp deletion of an adenine in exon
13 at codon 533 (533 delA) was identified. This microdeletion predicts a frameshift with premature termination of the protein 4 amino acids downstream from
the mutation (see Fig 1C).
Discussion
Previous studies have identified 22 different mutations
in patients with McArdle’s disease from different countries. These include nonsense, missense, and frameshift
mutations. By far the most common genetic error in
Caucasian patients is the R49X mutation, which was
observed by Tsujino and colleagues11 and El Schahawi
and colleagues28 in 55 of 72 US patients (76%) and in
92 of 144 alleles (64%); by Bartram and colleagues9 in
16 patients from the United Kingdom (100%) and in
26 of 32 alleles (81%); and by Vorgerd and colleagues15 in 6 German patients (66%) and in 10 of 18
alleles (56%). This mutation was distinctly less common in Mediterranean populations. Approximately
50% of Italian and Spanish patients had the R49X
mutation, accounting for 32% of mutant alleles (9 of
28 alleles and 12 of 38 alleles, respectively).26,27 These
results led some authors to suggest a North–South gradient for the R49X mutation across Europe. However,
we found the R49X mutation in 38 of 54 Spanish patients (70%), accounting for 55% of mutant alleles (59
of 108). This allele frequency is similar to that found
in patients from the United States (who had presumably mixed European ancestry) and Germany, lower
than that observed in patients from United Kingdom,
and higher than that reported in Italians and in a previous Spanish report. Our study includes the largest
number of European patients described so far, and
does not support the hypothesis of the existence of a
North–South gradient for the R49X mutation across
Europe. In Japanese patients, the R49X mutation has
never been encountered, and the most common mutation appears to be a deletion of a single codon 708/709
Martı́n et al: McArdle’s Disease
577
Fig 2. A schematic drawing of human glycogen phophorylase a. The polypeptide backbone is shown as a ribbon for the two subunits
of the dimer, one in blue, the other in green. The positions of the mutations discussed in this manuscript are shown in the blue
subunit with the atoms of the side chains at the site of mutations shown as orange sticks. The position of the active site is shown by
yellow balls representing the position of pirydoxal phosphate, the cofactor. The intersubunit allosteric effector site is represented by
the AMP (an intracellular ligand) molecule shown as pink balls. The position of the Ser 14 phosphate that regulates the activation
is shown nearby in magenta. This figure was prepared using InsightII software (Molecular Simulations, Inc, San Diego, CA).
in exon 17, which has never been reported in other
ethnic groups.25
The G204S mutation was less frequent, and found
in 8 of 54 patients (14.8%) and in 10 of 108 alleles
(9%). Tsujino and colleagues encountered this mutation in 20% of their series of patients and in 10% of
alleles (8 of 80).11 The W797R mutation was observed
in 16.5% of our patients (9 of 54), accounting for
13.7% of mutant alleles (15 of 108). This mutation
has only been reported in Spanish patients and seems
to be frequent in this population.20,30
The occurrence of multiple mutations explains the
relatively large number of patients who had different
mutations in the two alleles (ie, 21 patients were compound heterozygotes). In total, nearly 70% of our patients (37 of 54; 95% confidence interval:
57.5– 82.5%) had two mutant alleles harboring the
578
Annals of Neurology
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November 2001
R49X, G204S, or W797R mutations (ie, they were homozygous or compound heterozygous for any of the
three mutations), and only 12.7% (7 of 54 patients)
did not have any of the three mutations. Moreover, the
fact that 78% of mutant alleles among Spanish patients
(84 of 108 alleles; 95% confidence interval: 70 – 86%)
can be identified by PCR-RFLP analysis for the R49X,
G204S, and W797R mutations makes diagnosis possible through molecular genetic analysis of blood DNA,
thus avoiding muscle biopsy in a significant proportion
of patients.
We have identified six new molecular genetic defects
in patients with MPL deficiency: three missense mutations, two nonsense mutations, and one frameshift mutation. The missense mutations E348K, R601W, and
A703V would not be expected to directly influence the
binding of substrates or metabolic regulators judged by
Fig 3. (A) View of residues in the vicinity of Arg 193, which lies 6Å away from the AMP (an intracellular ligand) binding site. A
mutation at Arg 193 perturbs packing interactions at the dimer interface. A tryptophan residue at this position disrupts the intersubunit hydrogen bond network among Val 40, Lys 41, Glu 195, and Arg 193. Hydrogen bonds are indicated with dashed lines.
AMP is shown in pink. (B) View of residues in the vicinity of Arg 601. A tryptophan residue was modeled at residue 601 (yellow)
with a preferred sidechain rotamer at the approximate position of the arginine in the native enzyme. The amino acid replacement
disrupts hydrogen bonds normally formed between the sidechain of Arg 601 and residues Ser 788 and Gln 784. Hydrogen bonds
are indicated with dashed lines. (C) View of residues in the vicinity of Glu 348. A lysine residue was modeled at residue 348
(green) with a preferred sidechain rotamer pointing away from Arg 351 to minimize electrostatic repulsive interactions. The substitution disrupts normal ionic interactions that form among Glu 348 and Tyr 297, His 399 and Arg 351. Hydrogen bonds are indicated with dashed lines. (D) Space-filling representation. The polar sidechain atoms surrounding the buried Glu 348 sidechain
in red (center) are shown as R351 (blue), His 399 (light blue), and Tyr 297 (light brown). Main-chain atoms are gray, blue,
and red for carbon, nitrogen, and oxygen. Green sidechains are hydrophobic.
the spatial positions of the mutations. However, they
are likely to be the cause of MPL deficiency because
(1) they were the only nucleotide alteration in the coding region and adjacent exon/intron boundaries of the
PYGM gene, except for the heterozygous R49X mutation in the three cases; (2) they lead to the replacement
of amino acid residues that are highly conserved not
only in the glycogen phophorylases of various species
but also in the three human isoforms of this enzyme,31
which is consistent with a crucial role of these amino
acids in the normal function of MPL; and (3) 60 normal controls and 10 disease controls did not have any
of these mutations in their 160 alleles.
The E124X and Q754X nonsense mutations are
Martı́n et al: McArdle’s Disease
579
likely to cause premature termination of translation,
and to generate truncated 123-amino acid (R124X) or
753-amino acid (Q754X) peptides instead of the normal 841-residue PYGM protein. The 533 delA predicts
a frameshift and a premature termination of the protein 4 amino acids downstream of the mutation, leading to a deletion of 305 amino acids from the
C-terminal end of the PYGM protein. In these three
mutations, the difference in length of the resulting
peptides could be crucial for MPL function because the
abnormal enzyme proteins may be more prone to degradation.
We found the 753 delA mutation in 3 patients: 2
were siblings and compound heterozygotes for this mutation and for a 387 insA/del 8bp24; the other was a
compound heterozygote for the same mutation and for
the R49X mutation. This single-base deletion has been
found previously in 2 patients, one of Turkish origin14
and another of German background.15 These data suggest that the 753 delA mutation does not represent a
rare mutation in European patients with McArdle’s
disease. Another patient was homozygous for the
5⬘ivs14 g3a , which has already been reported in Caucasian patients with McArdle’s disease.12,18 This splicejunction mutation results in a 67-bp deletion in the
transcript, and leads to a frameshift containing a premature stop codon.12
The MPL protein exists as a homodimer containing
two identical subunits of molecular mass 97 kDa.
Based on the three-dimensional structure and positions
of regulatory and active sites residues, the enzyme
monomer can be divided into two domains, the
N-terminal and C-terminal domains.1,2 The N-terminal
domain extends from amino acid residue (aa) 1 to 482
and is referred to as the “regulatory” domain because it
contains the majority of ligand-binding residues. It also
contains all but one of the dimer contact residues. The
C-terminal residue (aa 482– 842) is referred to as the
“catalytic” domain because it contains the majority of
active site and pirydoxal phosphate-binding residues.
The active site cleft is located between the N- and
C-terminal domains. Of the 16 mutations in the
PYGM gene documented in this study (eight missense
mutations, three nonsense mutations, and four frameshift mutations), 6 reside within the N-terminal residue
and 10 within the C-terminal domain, suggesting that
this latter is more prone to mutation. A representation
of the three-dimensional structure of the MPL dimer
with the locations of the mutations is shown in Figure 2.
MPL is an elaborately regulated allosteric enzyme
that is subject to both positive and negative controls.
Intracellular ligands, such as AMP and glycogen, activate the enzyme by promoting formation of active conformers, whereas glucose, glucose-6-P, and purine
nucleosides inhibit activity by stabilizing inactive conformers.32,33 We carefully examined the sites of the
580
Annals of Neurology
Vol 50
No 5
November 2001
mutations found in this report in structures of both
active and inactive states of MPL. We substituted the
wild type amino acids with the mutated ones and observed the expected consequences using Insight software
(MSI Inc., San Diego, CA). Most of the mutations of
uncharged and solvent inaccessible residues and the
truncations must disrupt the basic structure of the protein. The mutations of charged residues would be expected to interfere with internal hydrogen-bonding
networks. There exist no significant differences in these
networks between the active and inactive states. The
R193W substitution is particularly interesting because
the mutation is only 6Å away from the AMP binding
site, and would affect the packing and hydrogen bonding network at the subunit interface (Fig 3A). The
E348K mutation is striking because the Glu sidechain
is intricately linked to other polar amino acids, all of
which are buried inside the protein, inaccessible to the
solvent. Mutation of the Glu would interfere with hydrogen bonding between the carboxylate and the
sidechains of Tyr 297, His 399, and Arg 351. A lysil
sidechain would introduce an electrostatic repulsion
with Arg 351 (see Fig 3C). Surprisingly, Arg 601 is
completely buried from solvent and its plus charge is
likely compensated for by Asp 564. The R601W missense mutation would eliminate hydrogen bonding of
the guanidinium with Gln 784, Asp 564, and Ser 788,
and it introduces a bulky hydrophobic residue at this
position that is expected to disrupt the local threedimensional structure (see Fig 3B). In summary, all the
mutations described in this paper either destroy the
structure of the enzyme by truncating the polypeptide
chain or by introducing severe incompatible partnering
that is caused by poor packing or electrostatic repulsions.
Supported by Fondo de Investigación Sanitaria, Ministerio de
Sanidad, Spain (FIS; 98/258 and 01/1426). M. A. Martı́n was supported by Sigma Tau, J. C. Rubio by FIS, and Y. Campos by the
Instituto de Salud Carlos III (98/3166).
We are indebted to Dr C. Kubisch for providing the primers to
sequence PYGM gene, and to Drs Aparicio, Arpa, Astarloa, Ballesteros, Bautista, Carrasco, Carrascosa, Cubillo, Garcı́a-Arroba,
Gutierrez-Rivas, Largo, Larrode, López-Pisón, Lorenzo, Macarrón,
Morillas, Sales, Sánchez, Torres, Torresana, Trueba, Tuņón,
Vı́lchez, Yebra, and Yusta for referring patients to us.
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correlation, molecular, heterogeneity, stud, deficiency, phenotypic, mcardle, myophosphorylase, disease, genotypes
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