DDHD1

Official Full Name

DDHD domain containing 1

Organism

Homo sapiens

GeneID

80821

Background

This gene is a member of the intracellular phospholipase A1 gene family. The protein encoded by this gene preferentially hydrolyzes phosphatidic acid. It is a cytosolic protein with some mitochondrial localization, and is thought to be involved in the regulation of mitochondrial dynamics. Overexpression of this gene causes fragmentation of the tubular structures in mitochondria, while depletion of the gene results in mitochondrial tubule elongation. Deletion of this gene in male mice caused fertility defects, resulting from disruption in the organization of the mitochondria during spermiogenesis. In humans, mutations in this gene have been associated with hereditary spastic paraplegia (HSP), also known as Strumpell-Lorrain disease, or, familial spastic paraparesis (FSP). This inherited disorder is characterized by progressive weakness and spasticity of the legs. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Synonyms

SPG28; PAPLA1; iPLA1I; PA-PLA1; iPLA1alpha;

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Detailed Information

DDHD structural domain-containing proteins belong to the intracellular phospholipase A1 (iPLA1) family and are predicted to be involved in phospholipid metabolism, lipid trafficking, membrane turnover, and signaling. Deletion of cardiolipin (CL), phosphatidylethanolamine and phosphatidylglycerol remodeling leads to Bart's syndrome and mitochondrial dysfunction. The DDHD1 gene, also known as DDHD domain-containing protein 1, is a recently discovered gene that has garnered significant attention in the scientific community due to its potential involvement in various physiological and pathological processes. The DDHD1 gene is a member of the DDHD (Disorder of Alanine Metabolism, D-Alanine-D-Alanine Ligase, Histidine Triad Nucleotide Binding Protein 1) domain family, which is characterized by a unique domain structure that binds to histidine triad motifs.

Structure and Function of DDHD1

The DDHD structural domain, originally found in the central portion of the Nir/rdgB (N-terminal structural domain interaction receptor/Drosophila retinal degeneration B) protein, is a 180 amino acid-long stretch of structural domain. The domain has four conserved amino acid residues (DDHD), from which the DDHD domain is named. The domain is also present in the C-terminal region of phosphatidic acid (PA) 3-precursor phospholipase A1 (PA-PLA 1). The DDHD structural domain is predicted to be involved in phospholipid metabolism, lipid trafficking, membrane turnover, and signaling (1). PA-PLA 1/DDHD1, KIAA0725p/DDHD2, and p125/Sec23ip are three mammalian iPLA 1 family members. iPLA 1 family proteins are also found in yeast, nematodes and plants.

Fig1. Gene structure of Ddhd1

Diseases of DDHD1

There are several reasons why it is important to understand the endogenous metabolic function of DDHD1. To begin with, deleterious mutations in human DDHD1 cause a rare neurological disorder called hereditary spastic paraplegia (HSP) subtype 28 (SPG28).Symptoms of SPG28 include spastic gait, hyperreflexia and mild penetrating peripheral neuropathy, cerebellar eye movements, and urinary incontinence. Other neurologic disorders associated with the mutation include juvenile amyotrophic lateral sclerosis and cerebral iron accumulating neurodegeneration. Therefore, understanding the lipid pathways regulated by DDHD1 in the central nervous system (CNS) may help to provide insight into the mechanistic basis of SPG28 and point the way to future therapeutic strategies for the disease. DDHD1 belongs to a small clade of sequence-associated serine hydrolases known as DDHD proteins, which also includes DDHD2 and SEC23IP. of note. loss-of-function mutations in DDHD2 result in a different form of HSP, SPG54, which manifests as limb spasticity/weakness and intellectual disability.

Apoptosis of DDHD1

Apoptosis is a process of programmed cell death that is essential for maintaining tissue homeostasis and eliminating damaged or unwanted cells. Dysregulation of apoptosis has been implicated in various pathological conditions, including cancer, inflammation, and neurodegenerative diseases. Recent studies have suggested that DDHD1 may play a role in regulating apoptosis. For instance, overexpression of DDHD1 has been reported to promote apoptosis in various cell lines, whereas silencing of DDHD1 expression has been shown to inhibit apoptosis.

References:

Yadav PK, Rajasekharan R. Misregulation of a DDHD Domain-containing Lipase Causes Mitochondrial Dysfunction in Yeast. J Biol Chem. 2016;291(35):18562-18581. doi:10.1074/jbc.M116.733378
Inloes JM, Jing H, Cravatt BF. The Spastic Paraplegia-Associated Phospholipase DDHD1 Is a Primary Brain Phosphatidylinositol Lipase. Biochemistry. 2018;57(39):5759-5767. doi:10.1021/acs.biochem.8b00810

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