An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy

Abstract

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7-1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micropolygria) due to a defect in the migration of neurons. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31. We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

“…FKRP mutations have been reported to cause WWS, congenital MD 1C, and LGMD2I, with the more severe clinical phenotypes typically being associated with mutations that further affect the glycosylation of a dystroglycan and laminin binding to a dystroglycan. 15e19 Mutations in FKRP and fukutin (FKTN ), the gene with which FKRP shares homology and from which FKRP got its name, 20,21 both can give rise to forms of either congenital MD or LGMD. 22,23 Recently, both FKRP and fukutin have been shown to possess ribitol 5-phosphate transferase activity, and a tandem ribitol 5-phosphate moiety was shown to be present on a dystroglycan on which laminin binding glycans could be synthesized and which are themselves absent in FKRP-, fukutin-, and isoprenoid synthase domain containingedeficient cells.…”

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

“…For example, FCMD was originally thought not to give rise to ocular findings. 13 This observation, however, was later attributed to the fact that most FCMD patients of Japanese descent share a common retrotransposonal insertion in the FCMD gene. This insertion, which occurs in the 3' untranslated region of the gene, causes reduced expression of normal fukutin protein, resulting in a milder phenotype than would occur from a null mutation.…”

“…49,50 Three 'mystery' genes exist, the function of which remains to be identified in the dystroglycanopathies: FCMD, FKRP and LARGE. FCMD mutations give rise to FCMD, which is a common form of CMD in Japan 13 and was the first CMD in which dystroglycan underglycosylation was demonstrated. 51 Fukutin protein is localized to the cis compartment of the Golgi apparatus, where it would be well positioned to affect the glycosylation of α-dystroglycan.…”

Gènes impliqués dans les alpha-dystroglycanopathies

“…L'insertion d'un rétrotransposon de 3 kb dans la région 3'UTR est responsable du syndrome de Fukuyama (FCMD), représentant la deuxième cause de dystrophie musculaire au Japon [39]. Cette mutation fondatrice explique le nombre de cas importants au Japon.…”