title: Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ¹-pyrroline-5-carboxylate synthase (P5CS).
abstract: We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Δ¹-pyrroline-5-carboxylate-synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1, c.1923 + 1G > A which results in the production of two anomalous transcripts that are predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype is characterized by diminished production of collagen types I and III, altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. This severe clinical and cellular phenotype overlaps with a broad group of neurocutaneous syndromes that include cutis laxa type II, wrinkly skin syndrome, de Barsy syndrome, and gerodermia osteodysplastica. 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.
authors: Department of Pediatrics, Maritime Medical Genetics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: David L
authors: DL
authors: Skidmore
authors: David
authors: D
authors: Chitayat
authors: Tim
authors: T
authors: Morgan
authors: Alek
authors: A
authors: Hinek
authors: Bjoern
authors: B
authors: Fischer
authors: Aikaterini
authors: A
authors: Dimopoulou
authors: Gino
authors: G
authors: Somers
authors: William
authors: W
authors: Halliday
authors: Susan
authors: S
authors: Blaser
authors: Yenge
authors: Y
authors: Diambomba
authors: Edmond G
authors: EG
authors: Lemire
authors: Uwe
authors: U
authors: Kornak
authors: Stephen P
authors: SP
authors: Robertson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D003241:Consanguinity; D003286:Contracture / Q000235:genetics; D003315:Cornea / Q000002:abnormalities / Q000601:surgery; D016039:Corneal Transplantation; D003483:Cutis Laxa / Q000175:diagnosis / Q000235:genetics*; D005145:Face / Q000002:abnormalities; D017809:Fatal Outcome; D016368:Frameshift Mutation; D006345:Heart Septal Defects, Ventricular / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009953:Ornithine-Oxo-Acid Transaminase / Q000235:genetics*; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D022821:RNA Splice Sites; D009953:Ornithine-Oxo-Acid Transaminase