Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Dysplasia mandíbuloacral types A and B (A and Mandibuloacral dysplasia types B) - Genes and ZMPSTE24 LMNA.

The mandibuloacral dysplasia is a disease that causes a variety of abnormalities involving bone development, pigmentation and fat distribution. People with this disease can grow slowly after birth. Most affected individuals are born with an underdeveloped lower jaw and small collarbone, leading to the characteristic features of a small chin and sloping shoulders. Other problems include bone acroosteolysis, delayed closure of certain bones of the skull and contractures. Additional signs and symptoms may include pigmentation mottle or uneven skin or other skin anomalies, progeria and metabolic disorders such as diabetes. A common feature of mandibuloacral dysplasia is lipodystrophy in certain regions of the body.

They described two types of mandibuloacral dysplasia: mandibuloacral dysplasia type A with lipodystrophy (MADA) and mandibuloacral dysplasia type B with lipodystrophy (MADB). Both types are distinguished by the pattern of distribution of fat throughout the body. On one hand, the type A described as partial lipodystrophy. Affected individuals have a loss of fatty tissue of the back and limbs, but can accumulate around the neck and shoulders. Usually, the type A begins in adulthood, although children may also be affected. On the other hand, Type B is a generalized lipodystrophy with loss of fat in the face, trunk and limbs. The B type starts early, often just after birth. Many newborns with type B are born prematurely.

The two forms of mandibuloacral dysplasia are due to mutations in different genes. Mutations in LMNA are responsible A (MADA), whereas mutations in the gene give rise to ZMPSTE24 type B (MADB). Inside the cells, these genes are involved in maintaining the structure of the nucleus and may play a role in many cellular processes.

LMNA, located on the long arm of chromosome 1 (1q22) encodes several proteins called slightly different laminae. The two main proteins, lamin A and lamin C are encoded in most cells in the body. These proteins have an almost identical amino acid sequence. Lamins A and C are intermediate filament proteins. Intermediate filaments provide stability and strength to the cells. Lamins A and C are components of the nuclear envelope. Specifically, these proteins are found in nuclear lamina. The nuclear envelope regulates the movement of molecules inside and outside the core, and is likely to play a role in regulating the expression of certain genes. Protein lamin A must be processed within the cell before becoming part of the lamina. Its initial form called prelamina A, is subjected to a complex series of steps that are necessary for the protein is inserted into the lamina. Lamina C does not have to undergo this treatment before joining the lamina.

They have identified at least four mutations in LMNA that give rise to type A mandibuloacral dysplasia (MADA). These mutations change amino acids in proteins lamin A and lamin of C. The most common mutation replaces the amino acid arginine for histidine at amino acid position 527 (Arg527His or R527H). Although the effects of LMNA mutations are not well known, amino acid changes may affect the structure of the protein lamin A or C or both lamina, and alter the way they interact with other proteins in the nuclear lamina. These changes are likely to alter the nuclear envelope, so the cells become more fragile. However, it is unclear how the altered lamina proteins contribute to the signs and symptoms of MADA.

The ZMPSTE24 gene, located on the short arm of chromosome 1 (1p34), encodes a protein that acts as a protease. ZMPSTE24 protein cleaves the immature version of the protein lamin A (prelamin A) in a particular place. This cleavage is an essential step in the maturation of lamin A. Lamin A mature is a component of the nuclear envelope, which regulates the movement of molecules inside and outside the nucleus, and is likely to play a role in regulation of the activity of certain genes.

They have identified at least four mutations in the gene give rise ZMPSTE24 the B type mandibuloacral dysplasia (MADB). These mutations lead to a reduction of ZMPSTE24 functional protein. Consequently, prelamina A is not processed efficiently, and accumulates in cells. In addition, a mature lamin A deficiency occurs. It is believed that these changes damage the core, causing the cells to become more brittle. However, it is unclear how mutations in the gene lead to ZMPSTE24 specific signs and symptoms of MADB.

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 detection of mutations associated with dysplasia mandibuloacral types A and B, by complete PCR amplification of the exons of the LMNA and ZMPSTE24 genes, respectively, and subsequent sequencing.

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).