Mutation in Pyrroline-5-Carboxylate Reductase 1 Gene in Families with Cutis Laxa Type 2

Abstract

Autosomal-recessive cutis laxa type 2 (ARCL2) is a multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. Cutis laxa includes a family of clinically overlapping conditions with confusing nomenclature, generally requiring molecular analyses for definitive diagnosis. Six genes are currently known to mutate to yield one of these related conditions. We ascertained a cohort of typical ARCL2 patients from a subpopulation isolate within eastern Canada. Homozygosity mapping with high-density SNP genotyping excluded all six known genes, and instead identified a single homozygous region near the telomere of chromosome 17, shared identically by state by all genotyped affected individuals from the families. A putative pathogenic variant was identified by direct DNA sequencing of genes within the region. The single nucleotide change leads to a missense mutation adjacent to a splice junction in the gene encoding pyrroline-5-carboxylate reductase 1 (PYCR1). Bioinformatic analysis predicted a pathogenic effect of the variant on splice donor site function. Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift. PYCR1 plays a critical role in proline biosynthesis. Pathogenicity of the genetic variant in PYCR1 is likely, given that a similar clinical phenotype has been documented for mutation carriers of another proline biosynthetic enzyme, pyrroline-5-carboxylate synthase. Our results support a significant role for proline in normal development.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…Furthermore, mutations in PYCR1 have been subsequently identified as described in De Barsy syndrome. 29,30 In addition, no prelamin A was detected by western blot in the patient's skin fibroblasts. In all, 60% of his fibroblasts' nuclei showed morphological abnormalities, including large aggregates or misdistribution of lamin A/C.…”

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…4,12,13,17,18,24,25,33 PCR products were Figure 2 Diagnostic flowchart for evaluation of a new CL patient with suspected autosomal recessive inheritance (non-type 1). The facial features of PYCR1, ALDH18A1 and GORAB-related syndromes are similar to each other and different from the ATP6V0A2-related ARCL2A.…”

“…Although the presentation of CCA is nonspecific, the combination of a CL syndrome with progeroid features and corpus callosum dysgenesis is highly suggestive. 12,17,20 So far, no brain anomalies have been reported in the patients diagnosed with MACS syndrome. The finding of periventricular cystic lesions in our patient (patient 1) diagnosed with a RIN2 mutation could be a coincidence, however, no suggestive perinatal history or vascular aberrations could be confirmed as an underlying basis of this feature.…”

“…This is in line with the findings of Kornak et al, demonstrating mitochondrial dysfunction, altered membrane potential and apoptosis rate, abnormal mitochondrial network on oxidative stress and ultrastructural changes by electomicroscopy. 18 In the medical literature, no metabolic abnormalities have been described in patients carrying PYCR1 mutations, however, out of the almost 30 reported patients [17][18][19][20][38][39][40][41] metabolic studies have been only performed in four cases.…”

“…2,15,16 The recently defined ARCL2B is caused by mutations in the PYCR1 gene, involved in de novo mitochondrial proline synthesis, leading to a progeroid appearance, parchment-like skin, triangular face, joint luxations, muscle hypotonia, dystonic posturing and developmental delay. 17,18 Some patients have normal intelligence. 19,20 Corpus callosum dysgenesis is common in ARCL2B.…”