title: A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.
abstract: There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. 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 P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.
authors.affiliation: Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: James
authors.initials: J
authors.lastname: Pitt
authors.forename: Salim
authors.initials: S
authors.lastname: Aftimos
authors.forename: Ram
authors.initials: R
authors.lastname: Ramadas
authors.forename: Marion A
authors.initials: MA
authors.lastname: Maw
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D003937:Diagnosis, Differential; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005808:Genes, Recessive; D018698:Glutamic Acid / Q000378:metabolism; D006639:Histidine; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020752:Neurocutaneous Syndromes / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D009520:New Zealand; D009953:Ornithine-Oxo-Acid Transaminase / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011392:Proline / Q000096:biosynthesis; D017386:Sequence Homology, Amino Acid
chemical_list: D018698:Glutamic Acid; D006639:Histidine; D011392:Proline; C000596432:ALDH18A1 protein, human; D000444:Aldehyde Dehydrogenase; D009953:Ornithine-Oxo-Acid Transaminase