Cause of genetic disease discovered

Mutated protein causes congenital joint contractures and intellectual disability

Arthrogryposis multiplex congenita is a disorder that is characterised by limitations of joint movement in different areas of the body. Contractures of the hand and foot joints are a particularly prominent feature of the disease. In severe cases, the entire body is affected. Scientists at the Max Planck Institute for Molecular Genetics in Berlin have identified a gene responsible for the disease: according to their findings, mutations in the ZC4H2 gene on the X chromosome cause AMC and intellectual disability.

Arthrogryposis multiplex congenita is a developmental disorder that arises during pregnancy and can be genetic in origin. The symptoms vary considerably. Different joints can be affected and malformations of the central nervous system can also arise. Some children affected by the disorder also have intellectual disability.

Scientists working with Vera Kalscheuer at the Max Planck Institute for Molecular Genetics in Berlin have now identified mutations of the zinc-finger gene ZC4H2 as the cause of AMC and intellectual disability. Mutations in this gene give rise to a highly variable clinical picture. The severity of the disease depends on the position of the mutated amino acid in the protein. If the substitution is in a position that plays an important role in the functioning of the protein, a so-called zinc-finger domain, the most severe form of the disease arises and the affected boys die in the early months or years after birth. Girls and women with a mutation in this gene or a complete loss of the gene on one of the two X chromosomes can also be affected.

The Berlin-based researchers discovered the first mutation in the ZC4H2 gene, a substitution of a single base in the DNA, in a family with Wieacker-Wolff syndrome. Symptoms of the affected include congenital contractures of the feet present at birth, progressive muscle atrophy, apraxia of the oculomotor muscles and muscles of facial expression, dysarthrias, and mild intellectual disability.

The disease is inherited via the X sex chromosome and the heterozygous women in this family are clinically unremarkable. ''We obtained an additional indication that ZC4H2 is a new disease gene through the investigation of a boy's mutated X chromosome. In this boy, a broken-out piece of the chromosome was re-inserted the other way around. As a result, the gene sequence of ZC4H2 was interrupted and the gene product was completely missing. In addition, we found mutations in the ZC4H2 gene in three other families with X-chromosomal inheritance of arthrogryposis,'' reports Kalscheuer.

The scientists then aimed to establish whether the ZC4H2 mutations are actually responsible for the symptoms. The zebrafish proved very helpful here as a genetic model organism. Zebrafish that do not have a zc4h2 gene product, swim at a significantly slower pace than those with a functioning one. If the gene product is restored, the fish swim again at their original speed.

As opposed to this, ZC4H2 with the mutations found in the families did not have any impact on the altered swimming behaviour. ''In fish without an active zc4h2 gene, the neurons of the spinal cord, which activate the muscular system and are responsible for muscle contraction, are damaged. They are shorter and less branched than their healthy counterparts. Moreover, they form fewer points of contact for controlling the muscular system and those that exist are less well organised than normal ones,'' explains Kalscheuer.

The researchers do not know the functions of the ZC4H2 protein yet. It belongs to a class of zinc-finger domain proteins that can bind to nucleic acids. Presumably, the protein zinc finger attaches itself to the DNA molecule and regulates other genes. ''It is possible that the protein also controls RNA molecules, which translate genetic information into proteins. It may also play a role in the transmission of signals at synapses between neurons or between neurons and muscle cells,'' says Kalscheuer.