A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model.

Cutis laxa (CL) is a rare genodermatosis, which is clinically and genetically heterogeneous. It is characterized by redundant, loose, sagging, and inelastic skin. In a consanguineous family from Lebanon with autosomal-recessive transmission, we identified a homozygous missense mutation (c.649T --> C; p.C217R) in the fibulin-5 gene (FBLN5), which was, to our knowledge, previously unreported. Small skin biopsies were performed, which permitted isolation of skin fibroblasts harboring this FBLN5 mutation; they exhibited a deficit in cell growth. A CL skin equivalent (CL-SE) model compared with control SE was successfully developed to define the behavior of CL fibroblasts in a three-dimensional model. There was increased cell death and a global extracellular matrix deficiency in the dermis of this CL-SE model, and a low level of the main elastic fiber expression. There was no basement membrane evident at the ultrastructural level, and type-VII collagen could not be detected at the histological level. This model reproduced some defects of the extracellular matrix and highlighted other defects, which occurred at the time of the basement membrane formation, which were not evident in skin from patients. This CL-SE model could be adapted to screen for therapeutically active molecules.

Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13.

We report clinical and molecular findings in 20 patients from 11 families with autosomal recessive congenital ichthyosis (ARCI) linked to chromosome 17p13, and attributed to mutations in the ALOX gene cluster, which includes three lipoxygenase genes, ALOXE3, ALOX12B, and ALOX15B. We identified six novel missense mutations and one novel deletion leading to a premature stop codon in ALOX12B in only six out of the 11 families which led us to investigate a possible implication of ALOX15B. Mutation analysis of this gene, as well as ALOXE3, which is known to be mutated in some cases of ARCI, failed to reveal causative mutations in the five remaining ARCI families, indicating that other genes on chromosome 17p13 may be involved in this disease. However, by adding new variants to the repertoire of ALOX12B mutations in non-bullous congenital ichthyosiform erythroderma, our data contribute to an enlargement of the spectrum of mutations for the development of efficient molecular genetic tests for analysis of at risk individuals whose carrier status is unknown.

L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.

l-2-Hydroxyglutaric aciduria (l-2-HGA) is characterized by progressive deterioration of central nervous system function including epilepsy and macrocephaly in 50% of cases, and elevated levels of l-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid (CSF). Nuclear magnetic resonance imaging shows distinct abnormalities. We report the identification of a gene for l-2-HGA aciduria (MIM 236792) using homozygosity mapping. Nine homozygous mutations including three missense mutations, two nonsense mutations, two splice site mutations and two deletions were identified in the gene C14orf160, localized on chromosome 14q22.1, in 21 patients from one non-consanguineous and 14 consanguineous Turkish families. We propose to name the gene duranin. Duranin encodes a putative mitochondrial protein with homology to FAD-dependent oxidoreductases. The functional role of this enzyme in intermediary metabolism in humans remains to be established.

Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis.

We report the genomic localization by homozygosity mapping and the identification of a gene for a new form of non-syndromic autosomal recessive congenital ichthyosis. The phenotype usually presents as non-bullous congenital ichthyosiform erythroderma with fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. A few patients presented a more generalized lamellar ichthyosis. Palmoplantar keratoderma was present in all cases, whereas only 60% of the patients were born as collodion babies. Six homozygous mutations including one nonsense and five missense mutations were identified in a new gene, ichthyin, on chromosome 5q33 in 23 patients from 14 consanguineous families from Algeria, Colombia, Syria and Turkey. Ichthyin encodes a protein with several transmembrane domains which belongs to a new family of proteins of unknown function localized in the plasma membrane (PFAM: DUF803), with homologies to both transporters and G-protein coupled receptors. This family includes NIPA1, in which a mutation was recently described in a dominant form of spastic paraplegia (SPG6). We propose that ichthyin and NIPA1 are membrane receptors for ligands (trioxilins A3 and B3) from the hepoxilin pathway.

Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2.

Lamellar ichthyosis type 2 (LI2) is a rare autosomal recessive skin disorder for which a gene has been localized on chromosome 2q33-35. We report the identification of five missense mutations in the ABCA12 gene in nine families from Africa affected by LI2. The mutations were homozygous in eight consanguineous families and heterozygous in one non-consanguineous family. Four of these mutations are localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABC proteins. The ABCA12 protein belongs to a superfamily of membrane proteins that translocate a variety of substrates across extra- and intracellular membranes. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3, a lamellar body membrane protein in lung alveolar type II cells, ABCA12 could function in cellular lipid trafficking in keratinocytes.

Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome.

Kindler syndrome is a rare autosomal-recessive genodermatosis characterized by bullous poikiloderma with photosensitivity. We report the localization to chromosome 20p12.3 by homozygosity mapping and the identification of a new gene, which we propose to name kindlerin. We found four different homozygous mutations in four consanguineous families from North Africa and Senegal; three are expected to lead to premature stop codons and truncated proteins and the fourth involves a splice site. We were unable to identify a mutation in kindlerin in a fifth consanguineous family from Algeria with a similar phenotype and in which the patient was homozygous for the markers in the 20p12.3 interval. The kindlerin protein contains several domains which are shared by a diverse group of peripheral membrane proteins that function as membrane-cytoskeleton linkers: two regions homologous to band 4.1 domain of which one includes a FERM domain with a NPKY sequence motif, and a third region with a PH or pleckstrin homology domain. Kindlerin might be involved in the bidirectional signaling between integrin molecules in the membrane and the cytoskeleton, and could be involved in cell adhesion processes via integrin signaling.

Novel mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1) and description of five ancestral haplotypes in patients with Mal de Meleda.

Mal de Meleda is a recessive, transgressive palmoplantar keratoderma for which we previously identified mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1). In this report we describe two new mutations: (i) a founder mutation, which changes a conserved cysteine residue to tyrosine (C99Y) in a large inbred Tunisian pedigree, and (ii) a signal sequence mutation (W15R), which was homozygous in a German family and heterozygous in a Scottish patient. Four ancestral haplotypes were observed in 69 patients from countries around the Mediterranean basin, and an additional haplotype was found in the German and Scottish patients.

Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1.

We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17. Linkage disequilibrium analysis of six families affected by NCIE permitted us to reduce a recently reported interval of 8.4 cM on chromosome 17p13.1 to a 600 kb region around the marker D17S1796, which contains LOX genes. LOX products have long been implicated in skin disorders. Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin. ALOXE3 and ALOX12B are two genes which are physically linked and functionally related. They are separated by 38 kb, have one more exon than the other LOX genes and are mainly expressed in epithelial cells including keratinocytes. Although the main substrate(s) of the two enzymes is (are) still unknown, the products of ALOX12B obtained in experimental systems have been demonstrated to be of R-chirality. It seems likely that the product of one of these enzymes may be the substrate of the other, and that they belong to the same metabolic pathway.