The most common mutation inFKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations

Abstract

Limb girdle muscular dystrophy (LGMD) is common in the Hutterite population of North America. We previously identified a mutation in the TRIM32 gene in chromosome region 9q32, causing LGMD2H in approximately two-thirds of the 60 Hutterite LGMD patients studied to date. A genomewide scan was undertaken in five families who did not show linkage to the LGMD2H locus on chromosome 9. A second LGMD locus, LGMD2I, was identified in chromosome region 19q13.3, and the causative mutation was identified as c.826C>A (L276I), a missense mutation in the FKRP gene. A comparison of the clinical characteristics of the two LGMD patient groups in this population reveals some differences. LGMD2I patients generally have an earlier age at diagnosis, a more severe course, and higher serum creatine kinase (CK) levels. In addition, some of these patients show calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia. None of these features are present among LGMD2H patients. A single common haplotype surrounding the FKRP gene was identified in the Hutterite LGMD2I patients. An identical core haplotype was also identified in 19 other non-Hutterite LGMD2I patients from Europe, Canada, and Brazil. The occurrence of this mutation on a common core haplotype suggests that L276I is a founder mutation that is dispersed among populations of European origin.

Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I

“…Our estimate of the average age of onset is about 24 years and there is a tendency for males to manifest signs and symptoms earlier and have higher serum CK values than females. 9 It is not surprising to us that the three boys and their mother, unlike the father, are not showing signs of muscular dystrophy, although we expect the disease to manifest eventually. There is also a large amount of variation within our LGMD2I cohort (24 patients); however, we estimate the average age at onset to be about 12 years (range 2 -25 years).…”

“…We genotyped individuals for the LGMD mutations and surrounding markers using previously published methods. 5,9 Further confirmation of mutant genotypes was obtained by sequencing both strands using a commercial sequencing service (The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada). Haplotypes were constructed manually by minimizing the number of recombinants and assuming no mutation of marker alleles.…”

“…8 A mutation in FKRP associated exclusively with the LGMD phenotype, c.826C4A (L276I), is particularly prevalent in Caucasian populations and we determined that this mutation is responsible for the second form of LGMD in Hutterites. 9 These two mutations appear to be responsible for all the LGMDs seen in the Hutterites.…”

Congenital Muscular Dystrophy

“…However, when amalgamating these results, it remains clear that FKRP mutations are the most frequently found in this group of conditions. We and others have previously published extensively on the spectrum of these mutations (128,205,211,258,(262)(263)(264)(265)(266)(267)(268)(269)(270)(271). (Figure 12 and Table 10).…”

Therapeutic Possibilities in the Autosomal Recessive Limb-Girdle Muscular Dystrophies

“…In LGMD2I, a founder mutation in fukutin-related protein (FKRP [C826A]) facilitates diagnosis. 11,85,86 The other forms of LGMD due to mutations in genes causing secondary reduction in alpha dystroglycan are more commonly associated with a congenital muscular dystrophy phenotype; however, these should be pursued for cases in which a reduction of alpha-dystroglycan is detected on muscle biopsy and mutation testing in FKRP is negative.…”