Type II autosomal recessive cutis laxa: Report of another patient and molecular studies concerning three candidate genes

Scherrer, Daniel; Alexandrino, Fabiana; Cintra, Maria Letícia; Sartorato, Edi Lúcia; Steiner, Carlos Eduardo

doi:10.1002/ajmg.a.32345

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…7,[16][17][18] Notably, there are numerous literature reports of cases resembling this suite of phenotypes, either unexplained or untested for the known genes. [19][20][21][22][23][24] In the course of regular clinical practice, we ascertained two Maritime Canadian pedigrees of French Acadian descent, one with four individuals diagnosed with ARCL2 and one with one such individual (Figures 1A and 1B). All of the patients displayed lax, wrinkled skin with reduced elasticity, lax joints, and mild craniofacial dysmorphic features ( Figure 2).…”

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confidence: 99%

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

Guernsey

Jiang

Evans

et al. 2009

The American Journal of Human Genetics

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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.

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confidence: 99%

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

Guernsey

Jiang

Evans

et al. 2009

The American Journal of Human Genetics

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“…Relatos menos constantes incluem coloboma macular, miopia e hipoplasia de íris. Nos membros, podem ser vistas outras anomalias secundárias como clinodactilia de quintos quirodáctilos e prega palmar única (1,4,12,14,15,17).…”

Section: As Várias Formas De Cutis Laxaunclassified

“…Em 2008, nosso grupo de estudo publicou os resultados das análises dos genes LOX, FBLN4 e FBLN5, não sendo identificadas mutações nos indivíduos com CLAR tipo II(17). No mesmo ano, Hennies et al(47), bem como, Kornak et controlam o formato, a adesão e a contração celular.…”

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