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Normal Function
The WDR45 gene provides instructions for making a protein called WD40 repeat protein interacting with phosphoinositides 4 (WIPI4). WIPI4 is a member of a group of proteins each with a characteristic structure resembling a seven-bladed propeller. The WIPI4 protein is involved in the early stages of a process called autophagy, which helps clear unneeded materials from cells, including excess amounts of an iron storage protein called ferritin. In autophagy, worn-out cell parts (such as organelles, which are specialized structures that perform certain tasks within the cell) and other materials that are no longer needed are isolated in tiny compartments called autophagosomes. The WIPI4 protein helps control (regulate) the production and elongation of autophagosomes to contain the materials. The autophagosomes are then transported to organelles called lysosomes, which act as recycling centers within cells. Lysosomes use digestive enzymes to break down waste substances and recycle worn-out cell components.
Health Conditions Related to Genetic Changes
Beta-propeller protein-associated neurodegeneration
More than 50 WDR45 gene mutations have been identified in people with beta-propeller protein-associated neurodegeneration (BPAN), a disorder that damages the nervous system. This damage leads to delayed development and recurrent seizures (epilepsy) beginning in infancy or early childhood, movement problems that get worse over time, and a gradual loss of intellectual functioning in adulthood. Affected individuals eventually have a buildup of iron in the brain that can be seen with medical imaging; for this reason, BPAN is classified as a type of disorder called neurodegeneration with brain iron accumulation (NBIA).
Most of the WDR45 gene mutations identified in people with BPAN are thought to result in the production of an unstable WIPI4 protein that is quickly broken down, leading to loss of WIPI4 protein function. Without functional WIPI4 protein, the process of autophagy is impaired, making cells less efficient at removing damaged organelles and waste materials. Researchers suggest that nerve cells (neurons) may be particularly vulnerable to impaired autophagy because they have long extensions (axons and dendrites), making it even more difficult to transport the waste materials from these structures to the lysosomes in the cell body for recycling. The waste materials can build up in these areas and damage them. Damage to neurons results in the neurological problems that occur in BPAN.
More About This Health ConditionOther Names for This Gene
- JM5
- NBIA4
- NBIA5
- WD repeat domain phosphoinositide-interacting protein 4 isoform 1
- WD repeat domain phosphoinositide-interacting protein 4 isoform 2
- WD repeat domain, X-linked 1
- WD repeat-containing protein 45
- WD45 repeat protein interacting with phosphoinositides 4
- WDRX1
- WIPI-4
- WIPI4
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Ebrahimi-Fakhari D, Saffari A, Wahlster L, Lu J, Byrne S, Hoffmann GF, Jungbluth H, Sahin M. Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain. 2016 Feb;139(Pt 2):317-37. doi: 10.1093/brain/awv371. Epub 2015 Dec 29. Citation on PubMed
- Haack TB, Hogarth P, Gregory A, Prokisch H, Hayflick SJ. BPAN: the only X-linked dominant NBIA disorder. Int Rev Neurobiol. 2013;110:85-90. doi: 10.1016/B978-0-12-410502-7.00005-3. Citation on PubMed
- Hayflick SJ, Kruer MC, Gregory A, Haack TB, Kurian MA, Houlden HH, Anderson J, Boddaert N, Sanford L, Harik SI, Dandu VH, Nardocci N, Zorzi G, Dunaway T, Tarnopolsky M, Skinner S, Holden KR, Frucht S, Hanspal E, Schrander-Stumpel C, Mignot C, Heron D, Saunders DE, Kaminska M, Lin JP, Lascelles K, Cuno SM, Meyer E, Garavaglia B, Bhatia K, de Silva R, Crisp S, Lunt P, Carey M, Hardy J, Meitinger T, Prokisch H, Hogarth P. beta-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain. 2013 Jun;136(Pt 6):1708-17. doi: 10.1093/brain/awt095. Epub 2013 May 17. Citation on PubMed or Free article on PubMed Central
- Nishioka K, Oyama G, Yoshino H, Li Y, Matsushima T, Takeuchi C, Mochizuki Y, Mori-Yoshimura M, Murata M, Yamasita C, Nakamura N, Konishi Y, Ohi K, Ichikawa K, Terada T, Obi T, Funayama M, Saiki S, Hattori N. High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. Neurobiol Aging. 2015 May;36(5):2004.e9-2004.e15. doi: 10.1016/j.neurobiolaging.2015.01.020. Epub 2015 Jan 30. Citation on PubMed
- Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. 2013 Apr;45(4):445-9, 449e1. doi: 10.1038/ng.2562. Epub 2013 Feb 24. Citation on PubMed
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