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Biochimica Et Biophysica Acta.... Feb 2020The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing... (Review)
Review
The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing the side chains of all conserved residues to the same side. PTS2 motifs are recognized by a bipartite protein complex consisting of the receptor PEX7 and a co-receptor. Cargo-loaded receptor complexes are translocated across the peroxisomal membrane by a transient pore and inside peroxisomes, cargo proteins are released and processed in many, but not all species. The components of the bipartite receptor are re-exported into the cytosol by a ubiquitin-mediated and ATP-driven export mechanism. Structurally, PTS2 motifs resemble other N-terminal targeting signals, whereas the functional relation to the second peroxisomal targeting signal (PTS1) is unclear. Although only a few PTS2-carrying proteins are known in humans, subjects lacking a functional import mechanism for these proteins suffer from the severe inherited disease rhizomelic chondrodysplasia punctata.
Topics: Amino Acid Motifs; Chondrodysplasia Punctata, Rhizomelic; Humans; Membrane Proteins; Peroxisomal Targeting Signal 2 Receptor; Peroxisomes; Protein Domains; Protein Structure, Quaternary; Protein Transport
PubMed: 31751594
DOI: 10.1016/j.bbamcr.2019.118609 -
Biochimica Et Biophysica Acta May 2016Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or... (Review)
Review
Peroxisomes contain numerous enzymatic activities that are important for mammalian physiology. Patients lacking either all peroxisomal functions or a single enzyme or transporter function typically develop severe neurological deficits, which originate from aberrant development of the brain, demyelination and loss of axonal integrity, neuroinflammation or other neurodegenerative processes. Whilst correlating peroxisomal properties with a compilation of pathologies observed in human patients and mouse models lacking all or individual peroxisomal functions, we discuss the importance of peroxisomal metabolites and tissue- and cell type-specific contributions to the observed brain pathologies. This enables us to deconstruct the local and systemic contribution of individual metabolic pathways to specific brain functions. We also review the recently discovered variability of pathological symptoms in cases with unexpectedly mild presentation of peroxisome biogenesis disorders. Finally, we explore the emerging evidence linking peroxisomes to more common neurological disorders such as Alzheimer's disease, autism and amyotrophic lateral sclerosis.
Topics: ATPases Associated with Diverse Cellular Activities; Animals; Brain; Disease Models, Animal; Gene Expression Regulation; Humans; Membrane Proteins; Metabolic Networks and Pathways; Mice; Mutation; Peroxisomal Disorders; Peroxisomes; Protein Isoforms; Protein Transport; Synaptic Transmission
PubMed: 26686055
DOI: 10.1016/j.bbamcr.2015.12.005 -
Dermatology Online Journal Nov 2010A seven-year-old girl was born with red, scaly skin that later evolved into hypopigmentation and follicular atrophoderma in a widespread distribution that followed...
A seven-year-old girl was born with red, scaly skin that later evolved into hypopigmentation and follicular atrophoderma in a widespread distribution that followed Blaschko lines. She also had patchy, scarring alopecia, left microphthalmia, bilateral cataracts, dysmorphic facies, short stature, hip dysplasia, and vertebral abnormalities. An elevated plasma 8(9)-cholestenol level confirmed the diagnosis of Conradi-Hünermann-Happle syndrome, which is caused by mutations in the emopamil binding protein (EBP) gene. This reports highlights the evolution of clinical findings over time in this X-linked dominant form of chondrodysplasia punctata.
Topics: Alopecia; Child; Cholesterol; Chondrodysplasia Punctata; Dermatologic Agents; Eczema; Female; Genetic Diseases, X-Linked; Humans; Hypopigmentation; Lactates; Mutation; Skin Diseases; Steroid Isomerases; Treatment Outcome
PubMed: 21163155
DOI: No ID Found -
The Application of Clinical Genetics 2018Chondrodysplasia punctata (CDP) is a skeletal abnormality characterized by premature calcification that is usually noticeable in the prenatal period and infancy.... (Review)
Review
Chondrodysplasia punctata (CDP) is a skeletal abnormality characterized by premature calcification that is usually noticeable in the prenatal period and infancy. Etiologically, the condition is heterogeneous, and the causes include fetal conditions such as chromosome abnormalities, peroxisomal disorders, lysosomal storage disorders, cholesterol synthesis defects and abnormal vitamin K metabolism, as well as maternal diseases such as severe malabsorption and exposure to teratogens. An association between CDP and maternal autoimmune disease was first observed and reported by Curry et al and Costa et al in 1993 and expanded by Chitayat et al in 2010. This review lists the clinical characteristics and radiologic findings of all cases reported to date in English and discuss the possible etiology of this interesting fetal finding.
PubMed: 29720879
DOI: 10.2147/TACG.S150982 -
Frontiers in Cell and Developmental... 2022Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in leading to impairment in plasmalogen (Pls) biosynthesis and...
A Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1.
Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in leading to impairment in plasmalogen (Pls) biosynthesis and phytanic acid (PA) oxidation. Pls deficiency is the main pathogenic factor that determines the severity of RCDP. Severe (classic) RCDP patients have negligible Pls levels, congenital cataracts, skeletal dysplasia, growth and neurodevelopmental deficits, and cerebral hypomyelination and cerebellar atrophy on brain MRI. Individuals with milder or nonclassic RCDP have higher Pls levels, better growth and cognitive outcomes. To better understand the pathophysiology of RCDP disorders, we generated an allelic series of mice either homozygous for the hypomorphic allele, compound heterozygous for the hypomorphic and null alleles or homozygous for the null allele. Pex7 transcript and protein were almost undetectable in the hypomorphic model, and negligible in the compound heterozygous and null mice. deficient mice showed a graded reduction in Pls and increases in C26:0-LPC and PA in plasma and brain according to genotype. Neuropathological evaluation showed significant loss of cerebellar Purkinje cells over time and a decrease in brain myelin basic protein (MBP) content in deficient models, with more severe effects correlating with genotype. All deficient mice exhibited a hyperactive behavior in the open field environment. Brain neurotransmitters analysis of deficient mice showed a significant reduction in levels of dopamine, norepinephrine, serotonin and GABA. Also, a significant correlation was found between brain neurotransmitter levels, the hyperactivity phenotype, Pls level and the severity of genotype. In conclusion, our study showed evidence of a genotype-phenotype correlation between the severity of deficiency and several clinical and neurobiochemical phenotypes in RCDP1 mouse models. We propose that PA accumulation may underlie the cerebellar atrophy seen in older RCDP1 patients, as even relatively low tissue levels were strongly associated with Purkinje cells loss over time in the murine models. Also, our data demonstrate the interrelation between Pls, brain neurotransmitter deficiencies and the neurobehavioral phenotype, which could be further used as a valuable clinical endpoint for therapeutic interventions. Finally, these models show that incremental increases in levels result in dramatic improvements in phenotype.
PubMed: 35898397
DOI: 10.3389/fcell.2022.886316