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PAFAH1B1 gene
URL of this page: https://medlineplus.gov/genetics/gene/pafah1b1/

PAFAH1B1 gene

platelet activating factor acetylhydrolase 1b regulatory subunit 1

Normal Function

The PAFAH1B1 gene (also known as LIS1) provides instructions for making a protein that is one part (subunit) of a complex called platelet-activating factor acetylhydrolase 1B (PAFAH1B). This complex regulates the amount of a molecule called platelet activating factor (PAF) in the brain. PAF is thought to be involved in directing the movement of nerve cells, a process known as neuronal migration. Proper neuronal migration is essential for normal brain development and function.

The PAFAH1B1 protein is also involved in the organization of the cell's structural framework (the cytoskeleton). This protein interacts with microtubules and with their associated proteins. Microtubules are the rigid, hollow fibers that make up the cytoskeleton; they play an important role in cell division and cell movement. Interactions between the PAFAH1B1 protein and the microtubules and their associated proteins are also essential for proper neuronal migration.

Health Conditions Related to Genetic Changes

Isolated lissencephaly sequence

Many variants (also called mutations) in the PAFAH1B1 gene have been found to cause isolated lissencephaly sequence (ILS), a condition characterized by abnormal brain development that results in the brain having a smooth surface (lissencephaly) instead of its normal folds and grooves. Individuals with ILS have severe intellectual disabilities and recurrent seizures (epilepsy) that begin in the first two years of life.

The PAFAH1B1 gene variants that cause ILS reduce the amount of functional protein available to help neurons in the developing brain migrate to their proper location. This impairs brain development and leads to the severe neurological problems seen in people with ILS.

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Subcortical band heterotopia

Several variants in the PAFAH1B1 gene have been found to cause subcortical band heterotopia. This condition causes abnormal brain development that results in signs and symptoms that are typically less severe than those seen in ILS. Some researchers consider these two conditions to be part of the same disease spectrum and use the term PAFAH1B1-related isolated lissencephaly sequence/subcortical band heterotopia to refer to both conditions. Individuals with subcortical band heterotopia typically have developmental delays, which can range from mild to severe. Additional signs and symptoms can include intellectual disabilities and seizures that may be drug-resistant.

Some variants in the PAFAH1B1 gene change single protein building blocks (amino acids) in the PAFAH1B1 protein, while other variants change the protein's length or structure. These variants alter the protein's ability to interact with microtubules and to form the PAFAH1B complex, both of which are needed for neuronal migration. Without proper neuronal migration, neurons in the developing brain can be misplaced, leading to the neurological problems seen in people with subcortical band heterotopia. 

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Miller-Dieker syndrome

A deletion of genetic material near the end of the short (p) arm of chromosome 17 causes Miller-Dieker syndrome. This region contains numerous genes, including the PAFAH1B1 gene. Signs and symptoms of Miller-Dieker syndrome include lissencephaly, intellectual disabilities, seizures, and distinctive facial features.

As a result of the deletion, people with this condition have only one copy of the PAFAH1B1 gene in each cell instead of the usual two copies. A deletion of one copy of the PAFAH1B1 gene in each cell reduces the amount of available PAFAH1B1 protein. Researchers believe that a shortage of this protein is responsible for the lissencephaly, intellectual disabilities, and seizures seen in people with Miller-Dieker syndrome.

Other deleted genes in the same region of chromosome 17 likely contribute to the other features of Miller-Dieker syndrome.

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Other Names for This Gene

  • LIS1
  • LIS2
  • MDCR
  • NudF
  • PAFAH
  • platelet-activating factor acetylhydrolase, isoform 1b, alpha subunit

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Brock S, Dobyns WB, Jansen A. PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia. 2009 Mar 3 [updated 2021 Mar 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK5189/ Citation on PubMed
  • Cardoso C, Leventer RJ, Ward HL, Toyo-Oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirotsune S, Wynshaw-Boris A, Dobyns WB, Ledbetter DH. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet. 2003 Apr;72(4):918-30. doi: 10.1086/374320. Epub 2003 Mar 5. Citation on PubMed or Free article on PubMed Central
  • Friocourt G, Marcorelles P, Saugier-Veber P, Quille ML, Marret S, Laquerriere A. Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly. Acta Neuropathol. 2011 Feb;121(2):149-70. doi: 10.1007/s00401-010-0768-9. Epub 2010 Nov 3. Citation on PubMed or Free article on PubMed Central
  • Fry AE, Cushion TD, Pilz DT. The genetics of lissencephaly. Am J Med Genet C Semin Med Genet. 2014 Jun;166C(2):198-210. doi: 10.1002/ajmg.c.31402. Epub 2014 May 23. Citation on PubMed
  • Gonzalez-Moron D, Vishnopolska S, Consalvo D, Medina N, Marti M, Cordoba M, Vazquez-Dusefante C, Claverie S, Rodriguez-Quiroga SA, Vega P, Silva W, Kochen S, Kauffman MA. Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders. PLoS One. 2017 Sep 27;12(9):e0185103. doi: 10.1371/journal.pone.0185103. eCollection 2017. Citation on PubMed or Free article on PubMed Central
  • Liu JS. Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep. 2011 Apr;11(2):171-8. doi: 10.1007/s11910-010-0176-5. Citation on PubMed
  • Saillour Y, Carion N, Quelin C, Leger PL, Boddaert N, Elie C, Toutain A, Mercier S, Barthez MA, Milh M, Joriot S, des Portes V, Philip N, Broglin D, Roubertie A, Pitelet G, Moutard ML, Pinard JM, Cances C, Kaminska A, Chelly J, Beldjord C, Bahi-Buisson N. LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity. Arch Neurol. 2009 Aug;66(8):1007-15. doi: 10.1001/archneurol.2009.149. Citation on PubMed
  • Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatr. 2009 Mar;98(3):421-33. doi: 10.1111/j.1651-2227.2008.01160.x. Epub 2008 Dec 16. Citation on PubMed
  • Wynshaw-Boris A. Lissencephaly and LIS1: insights into the molecular mechanisms of neuronal migration and development. Clin Genet. 2007 Oct;72(4):296-304. doi: 10.1111/j.1399-0004.2007.00888.x. Citation on PubMed

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