P5CS expression study in a new family with ALDH18A1‐associated hereditary spastic paraplegia SPG9

  title={P5CS expression study in a new family with ALDH18A1‐associated hereditary spastic paraplegia SPG9},
  author={Pamela Magini and Clara Marco-Mar{\'i}n and Juan M Escamilla-Honrubia and Diego Martinelli and Carlo Dionisi-Vici and Francesca Faravelli and Francesca Forzano and Marco Seri and Vicente Rubio and Emanuele Panza},
  journal={Annals of Clinical and Translational Neurology},
  pages={1533 - 1540}
In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia. In vitro production of the ALDH18A1 product, Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS), appeared necessary for cracking SPG9 disease‐causing mechanisms. We now describe a baculovirus–insect cell system that yields mgs of pure human P5CS and that has proven highly valuable with two novel P5CS mutations reported here in new SPG9B patients. We conclude that both mutations… 
Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia
The genetic and clinical spectrum of SPG9B caused by ALDH18A1 mutation is expanded, and new genetic variants to facilitate future diagnoses are defined to demonstrate the highly informative value of splicing mutation prediction in the characterization of disease-related intronic variants.
Δ1‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder
It is concluded that two neurocutaneous syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 syndrome are caused by essentially different spectra of ALDH18A1 mutations, which represent a continuum of increasing severity.
Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA.
A 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype is described, including novel neurological findings, which enlarges the neurological spectrum associated with this syndrome.
Structural basis of dynamic P5CS filaments
Cryo-electron microscopy reveals that filamentation is crucial for the coordination between the GK and GPR domains, providing a structural basis for the catalytic function of P5CS filaments.
The Multifaceted Roles of Proline in Cell Behavior
It is highlighted how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.
The Janus-like role of proline metabolism in cancer
A comprehensive review of proline metabolism in cancer is provided; the experimental evidence that links prolines metabolism with the different aspects of cancer progression and the potential mechanisms involved are collated.


ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism.
Results suggest that the pathway involving the enzyme encoded by ALDH18A1 (Δ1-pyrroline-5-carboxylate synthase, P5CS) is deficient, and it is shown that the enzymatic activity linked to one of the dominant mutations is deficient.
Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ1‐pyrroline‐5‐carboxylate synthase (P5CS)
The findings presented here emphasize the pleiotropic presentation of this group of conditions and suggest that multiple components of the extracellular matrix are perturbed in these disorders.
Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1.
Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment
Clinical and genetic findings in two Japanese families with SPG9B are obtained, extending the clinical and genetic spectrum of ALDH18A1-related disorders to include cerebellar ataxia and cognitive impairment.
Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.
Besides expanding the clinical spectrum of ALDH18A1-related pathology, mutations segregating in an autosomal dominant pattern are described, and amino acid chromatography is suggested in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases.
A missense mutation in ALDH18A1, encoding Δ1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome
In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5 CS was not affected by the H784Y substitution, suggesting that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.
Compound heterozygous mutations in two different domains of ALDH18A1 do not affect the amino acid levels in a patient with hereditary spastic paraplegia
This young man has spastic paraplegia with onset in childhood and temporal lobe epilepsy, but normal levels of proline, ornithine and arginine, which is the first case with compound heterozygous mutations affecting both P5CS domains, where levels of plasma amino acids have been reported.
Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain
This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.
Molecular Characterization of Carbamoyl‐Phosphate Synthetase (CPS1) Deficiency Using Human Recombinant CPS1 as a Key Tool
Glycerol partially replaces the essential activator N‐acetyl‐l‐glutamate (NAG), opening possibilities for treating CPS1D due to NAG site defects, and site‐limited proteolysis proved the correctness of the working model for the human CPS1 domain architecture generally used for rationalizing the mutations effects.