The ALDH18A1 gene provides instructions for making a protein known as P5CS. This protein is found in cell structures called mitochondria, which are the energy-producing centers of cells. P5CS appears to be important for mitochondrial function, and it plays a role in the formation (synthesis) of the protein building block (amino acid) proline.
The formation of proline is a multi-step process that converts the amino acid glutamate to the amino acid proline. The P5CS protein carries out the first step in this process by converting the amino acid glutamate to glutamate 5-semialdehyde. Subsequent steps convert this intermediate product to the amino acid proline. The conversion of glutamate to proline is important in maintaining a supply of the amino acids needed for protein production and for energy transfer within the cell.
Health Conditions Related to Genetic Changes
Variants (also known as mutations) in the ALDH18A1 gene can cause two different types of cutis laxa: autosomal dominant cutis laxa type 3 (ADCL3) and autosomal recessive cutis laxa type 3A (ARCL3A, which is also known as de Barsy syndrome). In autosomal dominant cutis laxa, one copy of the altered ALDH18A1 gene in each cell is sufficient to cause the characteristic features of the disorder. In autosomal recessive cutis laxa, both copies of the gene in each cell must be altered to result in the condition. These types of cutis laxa feature loose, wrinkled, and sagging skin that is often described as parchment-like; prominant veins; loose joints; clouding of the lenses of the eyes (cataracts) or other eye abnormalities; intellectual disability; and movement problems that can worsen over time. Autosomal recessive cutis laxa tends to be more severe than autosomal dominant.
Most ALDH18A1 gene variants involved in cutis laxa result in production of a P5CS protein with reduced activity. Some studies suggest that in ADCL3A, the abnormal protein from the altered copy of the gene interferes with the protein produced from the normal copy, further reducing the activity of this protein in cells. While the amount of proline is reduced in some people with ALDH18A1 gene variants, the levels are normal in other affected individuals. Impairment of the P5CS protein may disrupt mitochondrial function, which could lead to the death of skin and nerve cells. However, it is unclear exactly how changes in the ALDH18A1 gene lead to the particular signs and symptoms of cutis laxa.More About This Health Condition
Variants in the ALDH18A1 gene can cause autosomal dominant spastic paraplegia type 9A (SPG9A) and autosomal recessive spastic paraplegia type 9B (SPG9B). These conditions are part of a group of genetic disorders known as hereditary spastic paraplegias, which are characterized by muscle stiffness (spasticity) and the development of paralysis of the lower limbs (paraplegia) caused by breakdown of nerve cells that trigger muscle movement (motor neurons). Other features of SPG9A or SPG9B can include clouding of the lenses of the eyes (cataracts), developmental delay, or intellectual disability.
The ALDH18A1 gene variants are thought to reduce the function of the P5CS protein. Researchers suspect that impairment of the proline synthesis pathway hinders energy production in mitochondria, which may contribute to the death of neurons and lead to the progressive movement problems of SPG9A and SPG9B; however, the exact mechanism that causes these conditions is unknown.
Other Names for This Gene
- pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase)
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Bicknell LS, Pitt J, Aftimos S, Ramadas R, Maw MA, Robertson SP. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome. Eur J Hum Genet. 2008 Oct;16(10):1176-86. doi: 10.1038/ejhg.2008.91. Epub 2008 May 14. Citation on PubMed
- Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, Tao F, Konop J, Stoll M, Charles P, Jacoupy M, Matusiak R, Alonso I, Tallaksen C, Mairey M, Kennerson M, Gaussen M, Schule R, Janin M, Morice-Picard F, Durand CM, Depienne C, Calvas P, Coutinho P, Saudubray JM, Rouleau G, Brice A, Nicholson G, Darios F, Loureiro JL, Zuchner S, Ottolenghi C, Mochel F, Stevanin G. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015 Aug;138(Pt 8):2191-205. doi: 10.1093/brain/awv143. Epub 2015 May 29. Citation on PubMed
- Fischer-Zirnsak B, Escande-Beillard N, Ganesh J, Tan YX, Al Bughaili M, Lin AE, Sahai I, Bahena P, Reichert SL, Loh A, Wright GD, Liu J, Rahikkala E, Pivnick EK, Choudhri AF, Kruger U, Zemojtel T, van Ravenswaaij-Arts C, Mostafavi R, Stolte-Dijkstra I, Symoens S, Pajunen L, Al-Gazali L, Meierhofer D, Robinson PN, Mundlos S, Villarroel CE, Byers P, Masri A, Robertson SP, Schwarze U, Callewaert B, Reversade B, Kornak U. Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa. Am J Hum Genet. 2015 Sep 3;97(3):483-92. doi: 10.1016/j.ajhg.2015.08.001. Epub 2015 Aug 27. Citation on PubMed
- Panza E, Escamilla-Honrubia JM, Marco-Marin C, Gougeard N, De Michele G, Morra VB, Liguori R, Salviati L, Donati MA, Cusano R, Pippucci T, Ravazzolo R, Nemeth AH, Smithson S, Davies S, Hurst JA, Bordo D, Rubio V, Seri M. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. Brain. 2016 Jan;139(Pt 1):e3. doi: 10.1093/brain/awv247. Epub 2015 Aug 21. No abstract available. Citation on PubMed
- Zampatti S, Castori M, Fischer B, Ferrari P, Garavelli L, Dionisi-Vici C, Agolini E, Wischmeijer A, Morava E, Novelli G, Haberle J, Kornak U, Brancati F. De Barsy Syndrome: a genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction. Am J Med Genet A. 2012 Apr;158A(4):927-31. doi: 10.1002/ajmg.a.35231. Epub 2012 Mar 12. No abstract available. Citation on PubMed
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