Asphyxiating thoracic dystrophy; Jeune syndrome (asphyxiating thoracic dystrophy) - Genes CEP120, CSPP1, DYNC2H1, IFT80, IFT140, IFT172, TTC21B, WDR19, WDR34, WDR35 and WDR60.

Dystrophy asphyxiating thoracic, also known as Jeune syndrome is an inherited disorder of bone growth characterized by a small shorter thorax, short stature, and rib bones, arms and legs. Additional skeletal abnormalities may include pelvic bones and clavicles unusually shaped ends of long bones of the arms and legs in a cone shape, and polidactilia. Children with this condition are born with a narrow chest bell - shaped, which can limit the growth and expansion of the lungs. Respiratory problems threatening life, and most people live only in infancy or early childhood.

Some people with asphyxiating thoracic dystrophy have mild symptoms such as breathing difficulties rapid breathing or breathing difficulty. These people may live into adolescence or adulthood. Often, after infancy, people with this disorder develop kidney abnormalities that lead to malfunction of the kidneys. In addition, affected individuals may have heart defects and subglottic stenosis. Less common features asphyxiating thoracic dystrophy include the liver disease, pancreatic cysts, dental abnormalities, and an eye disease called retinal dystrophy that can cause loss of vision.

Mutations have been identified in at least 11 genes that can result asphyxiating thoracic dystrophy. Genetic changes in the IFT80 gene (intraflagellar transport 80) were the first to be associated with this disease. Later, it was discovered that mutations in another gene, DYNC2H1 (2 dynein heavy chain cytoplasmic 1), representing almost half of all cases. Mutations in other genes each represent a small percentage of all cases. These genes include: CEP120 (centrosomal protein 120, 5q23.2), CSPP1 (centrosome and spindle pole associated protein 1, 8q13.2), IFT140 (intraflagellar transport 140, 16p13.3), IFT172 (intraflagellar transport 172, 2p23.3 ), TTC21B (tetratricopeptide repeat domain 21B, 2q24.3), WDR19 (WD repeat domain 19, 4p14), WDR34 (WD repeat domain 34, 9q34.11), WDR35 (WD repeat domain 35, 2p24.1) and WDR60 ( WD repeat domain 60, 7q36.3). In total, about 70% of people with asphyxiating thoracic dystrophy have mutations in one of the known genes.

Genes associated with asphyxiating thoracic dystrophy encode the proteins found in the cilia. These proteins are involved in intraflagellar transport (IFT), which allows the materials are transported from and to the ends of the cilia. The IFT is essential for the establishment and maintenance of these cellular structures. Cilia play roles in several chemical signaling pathways, including the Sonic Hedgehog pathway. These pathways are important for growth, proliferation and cell differentiation. In particular, Sonic Hedgehog pathway appears to be essential for proliferation and differentiation of cells eventually give rise to cartilage and bone.

The IFT80 gene (intraflagellar transport 80), located on the long arm of chromosome 3 (3q25.33), encodes a protein which is located in the cilia. The IFT80 protein is part of a complex of proteins called complex IFT B. This complex helps transport material from the base to the tip of the cilia. Cilia are involved in cell movement and many different chemical signaling pathways. Cilia, also play an important role in the perception of sensory stimuli (such as sight, hearing and smell). They have identified at least 6 IFT80 gene mutations in people with asphyxiating thoracic dystrophy. Most of these mutations change amino acids in the protein IFT80, which results in an altered protein that causes malfunction IFT complex B. As a result, transportation of materials is stopped inside the cilia. It is believed that these changes in the IFT alter certain signaling pathways, including Sonic Hedgehog pathway, which may be the reason of abnormal bone growth asphyxiating thoracic dystrophy of. Although the reason is unknown, when the disease is due to mutations in the gene IFT80, usually associated with impaired bone growth.

The DYNC2H1 (2 dynein heavy chain cytoplasmic 1) gene, located on the long arm of chromosome 11 (11q21-q22.1), encodes a protein that is part of the complex dynein-2 proteins. The dynein-2 complex is located in the cilia. Specifically, dynein-2 is involved in intraflagellar transport (IFT), by which the materials are transported into the cilia. Specifically, dynein-2 is an engine using the energy of ATP molecule to feed the transport of materials from the end of the cilia to the base. They have identified more than 50 mutations in the gene DYNC2H1 in people with asphyxiating thoracic dystrophy. Mutations in this gene approximately half of all cases of this disease. Most known mutations change the amino acids in protein DYNC2H1. As a result, the complex dynein-2 made with the altered protein can not function normally, which interrupts IFT end of the cilia to the base and causes an accumulation of material at the end. It is believed that these changes in the IFT alter certain signaling pathways, including Sonic Hedgehog pathway, which may be the reason of abnormal bone growth asphyxiating thoracic dystrophy of. Although in some affected individuals asphyxiating thoracic dystrophy is also associated with abnormalities of the kidneys, liver, retina and other tissues when the disease is due to genetic mutations DYNC2H1, its characteristics are generally limited to problems with bone growth. The reasons for this difference are unknown.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with asphyxiating thoracic dystrophy, by complete PCR amplification of the exons of CEP120, CSPP1, DYNC2H1, IFT80, IFT140, IFT1 72, TTC21B, WDR19, WDR34, WDR35 genes and WDR60, respectively, and subsequent sequencing. We recommend starting the study by IFT80 and DYNC2H1 genes responsible for most cases of asphyxiating thoracic dystrophy.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).