1. ¹Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand
2. ²Genetic Health Services Victoria, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
3. ³Northern Regional Genetic Services, Auckland Hospital, Auckland, New Zealand
4. ⁴Whakatane Hospital, Whakatane, New Zealand
5. ⁵Department of Biochemistry, University of Otago, Dunedin, New Zealand

Correspondence: Professor S Robertson, Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin 9001, New Zealand. Tel: 64 3 479 7469; Fax: 64 3 479 7469; E-mail: stephen.robertson@stonebow.otago.ac.nz

Received 18 December 2007; Revised 26 March 2008; Accepted 3 April 2008; Published online 14 May 2008.

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 ¹-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.