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American Journal of Medical Genetics 72:363–368 (1997)
Limb Girdle Muscular Dystrophy in Manitoba
Hutterites Does Not Map to Any of the Known
LGMD Loci
Tracey Weiler,1 Cheryl R. Greenberg,2,3 Edward Nylen,1 Kenneth Morgan,4,5 T. Mary Fujiwara,4,5,6
M. Joyce Crumley,4,5 Teresa Zelinski,2,3 William Halliday,7 Barbara Nickel,1
Barbara Triggs-Raine,1,2 and Klaus Wrogemann1,2,3*
1
Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Manitoba, Canada
Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
3
Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
4
Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada
5
Montreal General Hospital Research Institute, Montreal, Quebec, Canada
6
Department of Pediatrics, McGill University, Montreal, Quebec, Canada
7
Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada
2
Limb girdle muscular dystrophy (LGMD) is
a heterogeneous group of disorders affecting primarily the shoulder and pelvic
girdles. Autosomal dominant and recessive
forms have been identified; 8 have been
mapped and 1 more has been postulated on
the basis of exclusion of linkage. An autosomal recessive muscular dystrophy was first
described in 1976 in the Hutterite Brethren,
a North American genetic and religious isolate [Shokeir and Kobrinsky, 1976; Clin
Genet 9:197–202]. In this report, we discuss
the results of linkage analysis in 4 related
Manitoba Hutterite sibships with 21 patients affected with a mild autosomal recessive form of LGMD. Because of the difficulties in assigning a phenotype in some
asymptomatic individuals, stringent criteria for the affected phenotype were employed. As a result, 7 asymptomatic relatives
with only mildly elevated CK levels were assigned an unknown phenotype to prevent
their possible misclassification. Two-point
linkage analysis of the disease locus against
markers linked to 7 of the known LGMD loci
and 3 other candidate genes yielded lod
scores of <-2 at u=0.01 in all cases and in
Contract grant sponsors: Medical Research Council of Canada;
Muscular Dystrophy Association of Canada; Manitoba Medical
Services Foundation; Canadian Genetic Diseases Network; Winnipeg Rh Institute Foundation; Children’s Hospital of Winnipeg
Research Foundation.
*Correspondence to: Klaus Wrogemann, MD, PhD, Department of
Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, MB, Canada R3E 0W3. E-mail: [email protected]
UMANITOBA.CA
Received 11 March 1997; Accepted 21 May 1997
© 1997 Wiley-Liss, Inc.
most cases at u=0.05. This suggests that
there is at least 1 additional locus for LGMD.
Am. J. Med. Genet. 72:363–368, 1997.
© 1997 Wiley-Liss, Inc.
KEY WORDS: LGMD; exclusion; limb girdle;
gene mapping; muscular dystrophy; Hutterite
INTRODUCTION
To date, 9 separate loci for limb girdle muscular dystrophy (LGMD) have either been mapped through linkage analysis or postulated to exist by exclusion of linkage. Two autosomal dominant LGMD loci (LGMD1A
and LGMD1B) were mapped to chromosome regions
5q31-q33 [Speer et al., 1992; Yamaoka et al., 1994] and
1q11-q21 [Van der Kooi et al., 1997] respectively. Autosomal recessive loci (LGMD2A-2F) were mapped to 6
chromosome regions: 15q15.1-q21.1 [Allamand et al.,
1995], 2p13.3 [Passos-Bueno et al., 1995a], 13q12-q13
[Ben-Othmane et al., 1992; Ben Othmane et al., 1995],
17q12-q21.33 [Roberds et al., 1994], 4q12 [Bönnemann
et al., 1995; Lim et al., 1995], and 5q33-q34 [PassosBueno et al., 1996]; a 7th locus has been postulated to
exist by exclusion to known loci [Passos-Bueno et al.,
1996]. Recently, Miyoshi myopathy (MM) was mapped
to chromosome region 2p12-p14 [Bejaoui et al., 1995],
and we and others have suggested that mutations at
the LGMD2B locus cause both MM and LGMD2B
[Bejaoui et al., 1995; Weiler et al., 1996]. Genes have
been identified for 5 of the 6 autosomal recessive loci:
mutations in the gene encoding calpain 3 (CANP3)
cause LGMD2A [Richard et al., 1995]; and mutations
in the genes encoding 4 components of the sarcoglycan
complex (a-, b-, g- and d-sarcoglycan) cause LGMD2D
[Roberds et al., 1994], LGMD2E [Lim et al., 1995; Bön-
364
Weiler et al.
nemann et al., 1995], LGMD2C [Noguchi et al., 1995],
and LGMD2F [Nigro et al., 1996], respectively.
Here we report the exclusion of 7 of the known
LGMD loci as causing LGMD in 4 Canadian Hutterite
families with an autosomal recessive form of LGMD.
One of the patients included in this study was in the
original description of muscular dystrophy in the Hutterites [Shokeir and Kobrinsky, 1976] (MIM [254110).
MATERIALS AND METHODS
Patients and Pedigree
We reconstructed a detailed pedigree on the basis of
information obtained from the initial publication
[Shokeir and Kobrinsky, 1976], Schmiedeleut family
records [Gross, 1996], our genealogical database (Fujiwara, Crumley, and Morgan, unpublished data), and
confirmatory interviews with the family (Fig. 1). Personal interviews and musculoskeletal examinations
were performed by CRG and consulting neurologists on
available relatives included in this study. Blood
samples were obtained from all consenting individuals
for DNA banking, Epstein Barr virus transformation,
creatine kinase (CK) analysis, and blood group serology. Electrophysiological studies, open muscle biopsies,
and echocardiographic assessments were performed
where feasible. Individuals were considered to be affected with LGMD if: (1) they exhibited signs and
symptoms of proximal muscle weakness with CK levels
ù4× normal in the absence of any other explanation for
CK elevation; (2) they exhibited signs and symptoms of
proximal muscle weakness and had a muscle biopsy
consistent with LGMD; or (3) their CK levels were
ù15× normal but they were asymptomatic. Individuals
were considered to be unaffected if they were symptomfree, had a normal musculoskeletal exam, and a normal
CK level. Individuals were assigned an unknown phe-
notype if their CK levels were > normal but ø4× normal and they were asymptomatic.
DNA Studies
DNA was extracted from whole blood as previously
described [Greenberg et al., 1987]. Oligonucleotide
primers designed to amplify 36 microsatellite loci
linked to 10 candidate loci, including DAG1, LGMD1A,
LGMD2A, LGMD2B, LGMD2C, LGMD2D, LGMD2E,
LGMD2F, SNT2B1, and SNT2B2 [Weber et al., 1991;
Ben-Othmane et al., 1992; Bashir et al., 1994; Fougerousse et al., 1994; Yamaoka et al., 1994; Allamand et
al., 1995; Passos-Bueno et al., 1995b; Lim et al., 1995;
Passos-Bueno et al., 1996], were obtained from Research Genetics, Inc. (Huntsville, AL). Markers linked
to LGMD1B were not tested because the location of this
disease gene only became known during review of this
paper. The chromosomal locations were obtained from
maps located in the Genome Database (web site: http:/
/gdbwww.gdb.org/). Genetic distances between candidate genes and linked markers were obtained from recent publications [Weber et al., 1991; Ben-Othmane et
al., 1992; Bashir et al., 1994; Fougerousse et al., 1994;
Yamaoka et al., 1994; Allamand et al., 1995; PassosBueno et al., 1995b; Lim et al., 1995; Passos-Bueno et
al., 1996]. DNA samples were genotyped according to
protocols reported elsewhere [Sirugo et al., 1992; Rodius et al., 1994] with minor modifications.
Linkage Analysis
Linkage analysis was performed on data obtained
from microsatellite typing of 18 patients, their parents,
and sibs available for study from 4 families using the
LINKAGE programs (versions 5.1 and 5.2) [Lathrop
and Lalouel, 1984] and the FASTLINK version (3.0P)
of the LINKAGE programs [Cottingham et al., 1993;
Schäffer et al., 1994]. MLINK was used for 2-point
Fig. 1. Pedigree of 21 Hutterite patients exhibiting LGMD, 18 of whom participated in the study. The pedigree includes the closest cousin relationships
between the parents of 4 LGMD families (A, B, C, and D) and the parents of patient 5, and at least 1 of the closest links between the families, thus not
all genealogical relationships are shown. Affected individuals are designated with solid symbols, unaffected individuals are designated with open symbols,
and 7 individuals with unknown phenotype are designated with grey symbols. Individuals whose DNA was used for microsatellite genotyping are
indicated with asterisks.
LGMD Does Not Map to Any Known Loci
analysis of an autosomal recessive trait with complete
penetrance. Disease allele frequency was estimated to
be 0.05 based on the number of known cases of LGMD
in Manitoba Hutterites. Marker allele frequencies were
assumed to be equal. No consanguinity or marriage
loops were used.
RESULTS
Pedigree and Clinical Description
Figure 1 shows 21 individuals (13 males and 8 females) who are highly suspected or confirmed to have
LGMD. Disease segregation is compatible with autosomal recessive inheritance. Clinical data from the 18
affected individuals assessed in this study are presented in Table I. Significant intra- and interfamilial
variability is evident. In families A and B, 3 of 14 individuals (patients 4, 9, and 10) have grossly elevated
CK levels (ù15× normal) but are asymptomatic and to
date, their muscle strength is preserved. A dystrophic
muscle biopsy was obtained on patient 4 confirming the
assignment of an affected phenotype. In symptomatic
individuals (patients 1–3, 5–8, 11–18), onset of muscle
weakness and easy fatigability generally were noted
from childhood to mid 30s and clinical progression
tended to be slow. Typically, patients complained of
365
different degrees of leg weakness and had difficulty
running, climbing stairs, and lifting objects. Six individuals indicated that they suffered neck and back
pain. All symptomatic patients demonstrated slender
proximal and distal muscle mass in their upper and
lower limbs without contractures. There was no evidence of facial muscle weakness in contrast to the reports by Shokeir and Kobrinsky [1976] and Shokeir
and Rozdilsky [1985]. Neither cardiomyopathy nor cardiac conduction defects were present in the patients
included in our study. Ataxia, fasciculations, muscle
cramps, sensory impairment, and myotonia were not
observed. All patients assessed had normal intellect,
bladder, bowel, and swallowing functions, and none
had an associated systemic illness or other disease.
Electromyographic studies have been primarily myopathic with some neurogenic characteristics in several
patients. Muscle biopsies were also compatible with a
dystrophic muscle process. In 1 patient who underwent
a muscle biopsy, grouping of small fibres raised the
possibility of a neurogenic component.
Genealogical Analysis
The ancestry of almost all of the contemporary Hutterites can be traced back to 89 founders (Fujiwara,
Crumley, and Morgan, unpublished data). Thus, the
TABLE I. Clinical Data of Patients With Limb Girdle Muscular Dystrophy
Patient no.
(Family)
Age at
onset (yr)
Age at
presentation (yr)
1(A)
25
32
2(A)
25
32
3(A)
4(A)
15–16
*
27
*
5(B)
mid 20s
53
6(B)
27
32
7(B)
8(B)
22
mid 20s
28
26
9(B)
10(B)
11(B)
*
*
18
*
*
21
12(C)
27
30
13(C)
14(C)
15
20
26
23
15(D)
8
45
Proximal weakness,
fatigue, falling
Muscle wasting &
weakness, back pain
Proximal weakness
Asymptomatic, past
history of carpal
tunnel syndrome
Proximal weakness,
waddling gait
Difficulty climbing
stairs, low back
pain, waddling gait
Weak legs
Neck pain, wasting
of shoulder girdle
Asymptomatic
Asymptomatic
Intermittent neck
pain
Proximal weakness,
fatigue
Proximal weakness
Proximal weakness,
low back pain
Back pain
16(D)
10
41
Proximal weakness
692
17(D)
11–13
34
943
18(D)
11–13
29
Proximal weakness,
fatigue
Proximal weakness,
fatigue
a
Presenting symptoms
CK
(U/L)a
Muscle biopsy
2,065
Present status
(age in years)
Ambulatory (37)
250
Dystrophic
Ambulatory (36)
922
2,975
Dystrophic
Ambulatory (27)
Asymptomatic (22)
317b
Myopathic
2,030
2,135
1,700
Myopathic
2,740
4,280
2,916
906
Myopathic
Ambulatory (28)
Ambulatory (26)
Asymptomatic (25)
Asymptomatic (23)
Ambulatory (21)
Dystrophic
Neurogenic,
myopathic
Myopathic
Ambulatory with
difficulty (36)
Ambulatory (33)
Ambulatory (29)
Dystrophic
Myopathic
Ambulatory with
difficulty (45)
Ambulatory with
difficulty (41)
Ambulatory (38)
797
3,160
1,092
Wheelchair (60)
Ambulatory (32)
Myopathic
Dystrophic
897
Highest recorded value; normal values for females: 28–116 U/L; normal values for males: 52–175 U/L.
CK reported 4× normal in 1976 [Shokeir and Kobrinsky, 1976].
*Asymptomatic, no data.
b
EMG
Myopathic
Ambulatory (35)
366
Weiler et al.
contemporary population of >30,000 can be considered
as 1 extended kindred. The Hutterite Brethren established 3 endogamous subdivisions, or leut (Dariusleut,
Lehrerleut, and Schmiedeleut), when they immigrated
to the US in the late 1870s. The Manitoba Hutterites
belong to the Schmiedeleut. We estimated the average
inbreeding coefficient of 10,693 Schmiedeleut considered to be in a 1981 census of our genealogical database
as 0.0338. The kinship coefficient of the parents (or the
inbreeding coefficient of a child) of Families A, B, C,
and D is 0.0172, 0.0651, 0.0452, and 0.0589, respectively. The kinship coefficient is largely due to the closest cousin relationship between the parents, and in
these families is 3rd cousins once-removed in 3 ways,
2nd cousins in 2 ways, 2nd cousins, and half-1st cousins once-removed, respectively (Fig. 1). Patient 5 has 2
affected sibs and is a parent of Family B. The parents
of patient 5 are most closely related as 1st cousins onceremoved and their kinship coefficient is 0.0522. There
are many more distant relationships that also contribute to the kinship coefficient. The total number of ways
the parents are related as cousins is 187, 223, 267, and
154 different ways. The average kinship coefficient of
the 24 pairs of parents who are not married to each
other is 0.0364 (range 4 0.0098 to 0.0880). There are at
least 10 ancestors born in the 1700s who could have
contributed an allele to each of the 8 parents of the
LGMD sibship and to the paternal grandparents of
Family B.
Linkage Analysis
Four families were tested for linkage of the disease
locus to 10 candidate loci on 9 chromosomes. These
include 7 of the currently mapped LGMD loci
(LGMD1A and LGMD2A–LGMD2F) as well as 3 genes
for 4 members of the dystrophin associated protein
complex (DAG1, SNT2B1, and SNT2B2) [IbraghimovBeskrovnaya et al., 1993; Ahn et al., 1996]. Lod scores
ø−2 were obtained for 15 markers (at least 1 marker
linked to each candidate locus) (Table II) suggesting
that each of the 10 candidate loci can be excluded as the
locus causing the disease in these families.
DISCUSSION
Given the genetic heterogeneity now clearly evident
in LGMD, one strategy is to study large consanguinous
kindreds where the parents of all affected individuals
are likely to carry copies of the same disease allele
identical by descent. The Hutterite families described
in this report represent such a kindred. Genealogical
analysis indicates that the parents of all patients in
this kindred can be traced back to 10 ancestors, 6 to 9
generations back, allowing us to consider the possibility that the disease in each of the patients is caused by
mutation(s) in the same gene.
Physical and laboratory examinations of individuals
from these 4 families have resulted in the identification
of 21 individuals with some or all of the symptoms of
LGMD, 3 of whom did not participate in this study.
Many of our findings on physical examination of symptomatic individuals confirm those of Shokeir and Kobrinsky [1976] and Shokeir and Rozdilsky [1985], including a waddling gait and difficulty in rising from a
squatting position (although we did not see any evidence of the facial muscle involvement that they had
reported). Because of the mild nature of the disease in
this kindred and the overlap between affected and normal individuals with respect to clinical phenotype and
serum CK elevation, we found it difficult to determine
reliably the clinical status of every individual. This is
especially so because serum CK, the most useful biochemical criterion of a muscular dystrophy, is a nonspecific finding and varies in any given individual.
High CK levels may also result, for example, from prolonged or weight-bearing exercise as well as from heatstroke, myocardial infarction, and acute renal failure
[Noakes, 1987]. Phenotypes were therefore defined
stringently to include only those individuals who had
extremely elevated CK levels (ù15× normal), or those
who were symptomatic either with CK ù4× normal or
a positive muscle biopsy. Using these criteria, patients
varied considerably in their clinical phenotype, from
completely asymptomatic to limited ambulation with a
walker. CK levels in our patients were also variable,
from 2× to 25× normal. Seven asymptomatic individu-
TABLE II. Lod Scores From Two-Point Linkage Analysis Between LGMD and Markers Linked to 10 Candidate Loci
Recombination fraction (u)
Candidate
locus
Marker
locusa
0.00
0.01
0.05
0.10
0.20
0.30
0.40
LGMD1A
LGMD2A
CSF1R
D15S182
D15S778
D2S291
D2S2109
D2S2111
D13S115
D17S806
D17S941
D4S1547
D4S1594
D5S470
D3S1766
D8S199
D16S266
−`
−`
−`
−`
−`
−`
−`
−`
−`
−`
−`
−`
−`
−`
−`
−4.53
−5.32
−5.75
−3.97
−3.47
−2.45
−9.28
−4.95
−2.16
−2.06
−6.48
−4.69
−5.80
−5.44
−10.22
−1.91
−2.63
−2.45
−1.96
−1.51
−1.14
−4.58
−2.28
−0.91
−0.74
−3.13
−2.52
−2.99
−2.68
−4.87
−0.93
−1.56
−1.20
−1.17
−0.77
−0.66
−2.71
−1.25
−0.47
−0.25
−1.82
−1.58
−1.81
−1.56
−2.78
−0.20
−0.64
−0.23
−0.49
−0.22
−0.27
−1.11
−0.43
−0.16
0.09
−0.72
−0.70
−0.76
−0.62
−1.03
0.00
−0.24
0.05
−0.19
−0.05
−0.11
−0.41
−0.13
−0.06
0.13
−0.26
−0.28
−0.29
−0.23
−0.33
0.02
−0.05
0.05
−0.04
0.00
−0.03
−0.09
−0.02
−0.01
0.05
−0.06
−0.06
−0.07
−0.05
−0.06
LGMD2B
LGMD2C
LGMD2D
LGMD2E
LGMD2F
DAG1
SNT2B1
SNT2B2
a
Markers were chosen on the basis of reported significant positive lod scores to the respective disease loci.
LGMD Does Not Map to Any Known Loci
als with mildly elevated CK were defined as ‘‘unknown’’ to prevent their misclassification.
The variation in phenotype may also be due to differences in the genetic background or the influence of
modifier gene(s). In fact, the involvement of a 2nd locus
in the determination of the clinical phenotype has been
suggested to play a role in 3 of the currently mapped
LGMDs (i.e., LGMD2A, LGMD2B, and LGMD2C)
[Richard et al., 1995; Weiler et al., 1996; McNally et al.,
1996; van Ommen, 1995; Beckmann, 1996]. Phenotypic
variation has also been observed for LGMD2B and
LGMD2C where severe and mild phenotypes are associated with a single haplotype [Weiler et al., 1996] and
a single mutation in g-sarcoglycan, D521-T, respectively [McNally et al., 1996].
Using a conservative definition of the affected phenotype, 2-point linkage analysis of the 12 microsatellite
loci linked to the known LGMD loci (LGMD1A,
LGMD2A–2F) yielded lod scores ø−2 at a recombination fraction of 0.01 and in some cases 0.05 (Table II).
This suggests that the disease in these families does
not map to any of the known LGMD loci. Since most
genes causing LGMD encode members of the dystrophin associated protein complex, we tested markers
linked to 3 genes encoding other members of the complex (DAG1, SNT2B1, and SNT2B2). Two-point linkage analysis of the disease versus these markers has
also yielded lod scores ø−2 which indicates that the
disease in these families does not map to any of these
loci either.
Our study suggests that there is at least 1 more locus
causing autosomal recessive LGMD, in agreement with
the report by Passos-Bueno et al. [1996]. The portion of
the pedigree illustrated here represents only 4 of the
Manitoba families with LGMD in the Schmiedeleut.
We know of 60 Hutterites exhibiting LGMD in Canada
from all 3 subdivisions. The additional families from
the other 2 subdivisions, who are more distantly related to the Manitoba families, will facilitate the mapping of the gene using an identity by descent approach.
This approach was successfully used to map a recessive
gene in the Mennonite population which has a population structure similar to that of the Hutterite population [Puffenberger et al., 1994]. The LGMD disease allele frequency in the Hutterite population appears to
be relatively high since there is no strong clustering
among the 4 Schmiedeleut families and the disease is
present in all 3 subdivisions of the population.
ACKNOWLEDGMENTS
We are indebted to the patients and their families for
their participation in this study. We thank Alejandro
Schäffer for providing the FASTLINK programs, Gail
Coghlan for genealogical information, and the many
referring doctors, consulting neurologists, and the surgeons who performed the muscle biopsies. This work
was supported by the Medical Research Council of
Canada (KW), Muscular Dystrophy Association of
Canada (KW), Manitoba Medical Services Foundation
(KW), Canadian Genetic Diseases Network (KM,
CRG), Winnipeg Rh Institute Foundation (TZ), and the
Children’s Hospital of Winnipeg Research Foundation
(TZ, CRG).
367
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