WDR45 Gene

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1		Hongliu Chen	+ 410 word(s)	410	2020-12-15 08:14:28

This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/wdr45

WD repeat domain 45.

genes

1. 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.

2. Health Conditions Related to Genetic Changes

2.1. 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.

3. Other 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

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.
Haack TB, Hogarth P, Gregory A, Prokisch H, Hayflick SJ. BPAN: the onlyX-linked dominant NBIA disorder. Int Rev Neurobiol. 2013;110:85-90. doi:10.1016/B978-0-12-410502-7.00005-3. Review.
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, Héron D, Saunders DE, Kaminska M, Lin JP, Lascelles K, Cuno SM, MeyerE, Garavaglia B, Bhatia K, de Silva R, Crisp S, Lunt P, Carey M, Hardy J,Meitinger T, Prokisch H, Hogarth P. β-Propeller protein-associatedneurodegeneration: a new X-linked dominant disorder with brain iron accumulation.Brain. 2013 Jun;136(Pt 6):1708-17. doi: 10.1093/brain/awt095.
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-propellerprotein-associated neurodegeneration (BPAN) among patients with intellectualdisability and young-onset parkinsonism. Neurobiol Aging. 2015May;36(5):2004.e9-2004.e15. doi: 10.1016/j.neurobiolaging.2015.01.020.
Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-YoshidaE, 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 ofchildhood with neurodegeneration in adulthood. Nat Genet. 2013 Apr;45(4):445-9,449e1. doi: 10.1038/ng.2562.

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Hongliu Chen

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Update Date: 24 Dec 2020

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