Perrault syndrome ... (Perrault syndrome) - Genes C10orf2, CLPP, HARS2, LARS2, or HSD17B4.
Perrault syndrome is a rare disease that causes different patterns of signs and symptoms in men and women affected. A key feature of this disease is hearing loss that occurs in both men and women. Affected women also have abnormalities of the ovaries. Moreover, in some affected people develop neurological problems.
Perrault's syndrome, hearing problems are due to sensorineural hearing loss. The general decline affects both ears and can be present at birth or in early childhood begin. Unless the hearing is fully impaired at birth, hearing problems worsen over time. Women with Perrault syndrome have abnormal ovaries or ovarian dysgenesis, although external genitalia are normal. Girls seriously affected by the disease have primary amenorrhea and most never have a menstrual period. Less affected women with primary ovarian failure , and although their menstrual periods begin in adolescence, are becoming less frequent and eventually stop having menstrual periods before age 40. In addition, women with Perrault syndrome may have difficulty conceiving or they are infertile. On the other hand, neurological problems in those affected may include mental retardation, ataxia and peripheral neuropathy. However, not all people with this disease have neurological problems.
Perrault syndrome is due to mutations in C10orf2, CLPP, HARS2, or HSD17B4 LARS2 genes. These genetic changes have been identified in a small number of individuals affected.
The C10orf2 gene, located on the long arm of chromosome 10 (10q24), encoding two similar proteins called "Twinkle" and "Twinky" localized in mitochondria. Mitochondria contain mitochondrial DNA (mtDNA), essential to normal function. The "Twinkle" protein is involved in the production and maintenance of mtDNA, functioning as a helicase mitochondrial DNA. The role of "Twinky" protein is unknown. They have identified at least 4 C10orf2 gene mutations in families with Perrault syndrome. The mutations involved in the individual amino acids change Twinkle protein, which alters the helicase activity of the protein. However, it is unclear how genetic mutations cause C10orf2 the hearing and ovarian abnormalities in affected individuals.
The CLPP gene, located on the short arm of chromosome 19 (19p13.3), encoding the protein subunit ClpP. Multiple copies of this protein interact to form the complex ClpP. This complex is one of two parts of the ClpXP protease which breaks down proteins abnormally folded. The other part of the protease ClpXP called the ClpX complex displays abnormal proteins and includes in the compartment formed by the ClpP complex, where they decompose into small fragments. The ClpP complex found in mitochondria. They have identified at least 3 CLPP gene mutations in families with Perrault syndrome. These genetic changes are likely to alter the structure of the chamber formed by the ClpP complex, which may affect the breakdown of misfolded mitochondrial proteins that could affect mitochondrial function. However, it is unclear how these changes cause the characteristics of Perrault syndrome.
The HARS2 gene, located on the long arm of chromosome 5 (5q31.3), encoding the enzyme histidyl-tRNA synthetase mitochondrial. This enzyme is important in protein synthesis in mitochondria. During protein synthesis, either in the mitochondria or in the cytoplasm tRNA helps assemble amino acids in a protein chain form. Each tRNA carries a specific amino acid to the growing chain. The aminoacyl-tRNA synthetases enzymes including mitochondrial histidyl-tRNA synthetase, bind a particular tRNA with a specific amino acid. Histidyl-tRNA synthetase mitochondrial binds the amino acid histidine to correct tRNA, which helps ensure that histidine is added at the appropriate place in the mitochondrial protein. They have identified at least two mutations in the gene HARS2 associated with Perrault syndrome. These genetic changes reduce the activity of the mitochondrial tRNA synthetase histidyl-. Deficiency histidyl-tRNA synthetase mitochondrial function prevents the normal assembly of new proteins in the mitochondria. Although it is likely that the set of altered proteins disrupts mitochondrial energy production, it is not clear how HARS2 genetic mutations lead to hearing problems and ovarian abnormalities affected individuals.
The LARS2 gene, located on the short arm of chromosome 3 (3p21.3), encodes an enzyme called leucyl-tRNA synthetase mitochondrial. This enzyme is important in protein synthesis in mitochondria. While in most cases the protein synthesis in the cytoplasm occurs, some proteins are synthesized in the mitochondria. During protein synthesis, either in the mitochondria or in the cytoplasm tRNA helps constitute amino acids in a protein chain form. Each tRNA carries a specific amino acid to the growing chain. Aminoacyl-tRNA synthetases, including mitochondrial leucyl-tRNA synthetase, bind a particular tRNA with a specific amino acid. Leucyl-tRNA synthetase mitochondrial binds the amino acid leucine to the correct tRNA, which helps ensure that the leucine is added in the appropriate place in the mitochondrial protein. They have identified at least 3 mutations in the gene LARS2 individuals with Perrault syndrome. These genetic changes reduce or eliminate the mitochondrial activity of leucyl-tRNA synthetase. Deficiency leucyl-tRNA synthetase mitochondrial function prevents the normal assembly of new proteins in the mitochondria. It is likely that the entire altered protein disrupts mitochondrial energy production. However, it is unclear how genetic mutations generate LARS2 hearing problems and ovarian abnormalities affected individuals.
The HSD17B4 gene, located on the long arm of chromosome 5 (5q21), encoding the protein-D bifunctional. This protein is an enzyme, which means that helps specific biochemical reactions take place. Bifunctional protein-D is in the peroxisomes which contain a variety of enzymes that break down many different substances. Bifunctional protein-D is involved in the breakdown of fatty acids. This protein has two domains with enzymatic activity, hydratase and dehydrogenase domains. These domains help carry out the second and third steps, respectively, a process called peroxisomal beta-oxidation of fatty acids. This process shortens the fatty acid molecules on two carbon atoms in each stage until the fatty acids are converted into acetyl-CoA molecule, which is transported to the outside of peroxisomes for reuse by the cell. They have been associated with at least two genetic mutations HSD17B4 Perrault syndrome. These mutations reduce the amount of functional protein-D bifunctional encoded. However, it is unclear what effect these mutations in the breakdown of fatty acids in individuals affected or how mutations lead to signs and symptoms of Perrault syndrome.
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 Perrault syndrome by complete PCR amplification of the exons of C10orf2, CLPP, HARS2, and HSD17B4 LARS2 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).