A research team at the Max Planck Institute of Neurobiology in Martinsried/Germany has discovered a new genetic cause for muscular dystrophy. The scientists unraveled a destablizing defect in muscle structures that were not previously implicated in muscle diseases. The subtle disturbance of muscle fibre architecture identified in three Brasilian families may play an important role in other patients with similar disorders including age-related deterioration of heart and limb-girdle muscles. Identification of telethonin as a disease-causing gene will help improve diagnosis and therapeutic strategies for degenerative muscle disorders. The report will be published in the February issue of Nature Genetics.
Muscular dystrophies form a large group of clinically similar diseases characterized by progressive muscle weakness and degeneration. There are many rare forms with various onset, time course, severity and involvement of particular muscles. Some forms appear early in childhood, other forms late in adolescence or adulthood. Although most forms are regarded as being caused by distinct genetic factors, only 30% of muscular dystrophies can be related to defined genetic defects.
The biggest challenge for geneticists are those recessively inherited muscular dystrophies that seem to occur as isolated cases in different families. Although the patients suffer from very similar patterns of muscular weakness beginning in the hips and shoulders, the genetic causes for these slowly progressing disorders are heterogenous and hard to identify. Small families in modern industrial societies with one affected child and perhaps a second healthy sib are not a good starting point to chase after a rare defect in the human genome.
To understand this dilemma, we need to recall the basic laws of inheritance as discovered by Gregor Mendel more than 100 years ago. Recessively inherited traits and diseases can only manifest themselves if both parents carry the specific gene variant. The probability of transmitting both critical copies (mutant alleles) to an offspring is 25%. A recessive disease can be suggested if at least two children are affected in the same family. If different recessive defects result in very similar disease manifestations like in disorders of muscle degeneration, small families cannot be pooled and treated as a homogenous group in genetic studies. The success of such studies then depends on single large families with many affected children. Since only a quarter of children on average develop the disease over years, the number of informative unambiguous cases is always low. The probability to find a family with eight children of which six suffer from the disease is extremely low, not only because such families with these diseases and eight children are so rare, but also because only two out of eight children on average are expected to acquire both dysfunctional copies from their parents. The probability that such a couple has six or more affected children among eight offsprings is about 1 in a 1000 and even then the fraction of the human genome which needs to be searched through for the defect remains pretty large.
For these reasons it is not so surprising that a new form of limb girdle muscular dystrophy was first discovered in a large Brasilian family by a research team in Sao Paulo, Brasilia, three years ago. Hereditary diseases were not known in the parents or their relatives, but nevertheless six out of eight children were struck down by a new form of muscular dystrophy. Bringing up six children suffering from this progressive disease can only be considered a nightmare, but the sophisticated analysis of this family has lead to an important medical breakthrough.
The Brasilian research team headed by M. Rita Passos-Bueno was first able to draw clear dividing lines between this muscular disease and other limb girdle muscular dystrophies and to localize the genetic defect in a new area on chromosome 17. Because of the small number of informative family members it was not possible to define narrow boundaries for the region of interest.
Fortunately, Dieter Jenne from the Department of Neuroimmunologiy at the Max Planck Institute of Neurobiology and his technicians Heike Reimann, Antje Nilforoushan and Lisa Stegmann, have developed an almost complete physical map with many landmarks and milestones for this large portion of chromosome 17 last work. This work opened him the way to identify and assemble most of the genes from this region using many bits of information that are deposited in various databases of the internet like pieces of an unsolved huge jigsaw puzzle. In the end he was convinced of having identified one little mosaik piece for which six of the eight children had inherited two bad copies from their parents.
The predicted alteration of the mosaik piece was subsequently verified and conclusively demonstrated in a collaboration with Dr. Rita Passos-Bueno. Muscle biopsies and blood samples from patients were further investigated to disclose the complete absence of a small muscle protein whose DNA sequence was first reported by an Italian research group and named telethonin in honour of the Italian Telethon foundation.
The gene encoding telethonin evolved very late during vertebrate evolution. It is probably restricted to mammalian species and is the smallest muscle specific protein (19 kDa) known so far. Its protein levels are regulated by a variety of stimuli and endogenous factors. It sits like a cap on top of the largest known protein titin and shields the vulnerable end of this gigantic filamentous protein. For this reason it is also called T-cap in very recent publications. It most likely functions as an assembly and stabilization factor in longitudinal direction at the interface (Z-disc) between the smallest contractile units of a muscle fibre.
The current discovery of a causal relationship between mutations in the telethonin gene and a new form (LGMD2G) of limb girdle muscular dystrophy provides new diagnostic and therapeutic strategies for degenerative muscle diseases. Screening for faulty telethonin copies will permit an early definite diagnosis and a solid genetic counseling of families with one affected child. Overproduction of telethonin by somatic gene therapy may mitigate the severity and breakdown of muscle tissue in patients with specific telethonin defects, but patients suffering from other forms of muscular dystrophies may also benefit from telethonin-based new therapies.
Eloisa S. Moreira, Tim J. Wiltshire, Georgine Faulkner, Antje Nilfouroshan, Mariz Vainzof, O. Suzuki, G.Valle, Roger Reeves, Mayana Zatz, M. Rita Passos-Bueno, Dieter E. Jenne: "Limb-Girdle Muscular Dystrophy type 2G (LGMD 2G) is caused by mutations in the gene encoding the sarcomeric protein telethonin", Nature Genetics, volume 24, No. 2, February 2000
Further information or on the internet: www.dmd.nl
Published: 31-1-2000 Contact: Dieter Jenne Max Planck Institute for Neurobiology, Martinsried near Munich, Germany E-Mail: djenne@neuro.mpg.de Phone: 49-89-8578-3588 Fax: 49-89-8578-3790
Journal
Nature Genetics