Peeling skin syndrome is a heterogeneous group of rare disorders.
P
eeling skin,
l
eukonychia,
a
cral punctate keratoses,
c
heilitis and
k
nuckle pads (PLACK syndrome, OMIM616295) is a newly ...described form of PSS with an autosomal recessive mode of inheritance. We report a 5.5-year-old boy with features of PLACK syndrome. Additionally, he had mild cerebral atrophy and mild muscle involvements. Whole exome sequencing was performed in genomic DNA of this individual and subsequent analysis revealed a homozygous c.544G > T (p.Glu182*) nonsense mutation in the
CAST
gene encoding calpastatin. Sanger sequencing confirmed this variant and demonstrated that his affected aunt was also homozygous. Real-time qRT-PCR and immunoblot analysis showed reduced calpastatin expression in skin fibroblasts derived from both affected individuals compared to heterozygous family members. In vitro calpastatin activity assays also showed decreased activity in affected individuals. This study further supports a key role for calpastatin in the tight regulation of proteolytic pathways within the skin.
Summary
Acral peeling skin syndrome (APSS) is a rare autosomal recessive condition, characterized by asymptomatic peeling of the skin of the hands and feet, often linked to mutations in the gene ...TGM5. However, more recently recessive loss of function mutations in CSTA, encoding cystatin A, have been linked with APSS and exfoliative ichthyosis. We describe the clinical features in two sisters with APSS, associated with a novel large homozygous deletion encompassing exon 1 of CSTA.
Netherton syndrome (NS MIM
256500) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic ...manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Iα, the α subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor β2, and the diastrophic dysplasia sulfate–transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.
Summary A new variant of congenital exfoliative ichthyosis in two related Bedouin families is reported. The ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the ...palms and soles. The prominent well‐demarcated areas of denuded skin in moist and traumatized regions resembled the ‘mauserung’ phenomenon of ichthyosis bullosa of Siemens (IBS). Unlike in IBS, epidermolysis is absent on histological examination. Electron microscopy revealed a prominent intercellular oedema and numerous aggregates of keratin filaments in basal keratinocytes. Abnormal keratin (K) 1 expression was seen in the affected epidermis; however, all other keratins, including K2e, had a distribution comparable to that seen in normal controls. A maximum two‐point LOD score of 2·53 and multipoint LOD score of 3·76 were obtained for marker D12S390, suggesting linkage to the type II keratin cluster on chromosome 12q13. Sequencing of both the K1 gene, the promotor and the 3′ calcium regulatory region did not reveal a mutation. K2e and K5 genes, as well as the genes harboured within the minimal region, such as retinoic acid receptor γ, sterol O‐acyltransferase 2, integrin β7 and insulin‐like growth factor binding protein‐6, were also excluded. This combination of clinical, histological, ultrastructural and genetic features has not been previously reported in other congenital exfoliative ichthyoses. We therefore suggest that it represents a new form of exfoliative ichthyosis.
Involvement of GJB2 noncoding regions in hearing loss (HL) has not been extensively investigated. However, three noncoding mutations, c.-259C>T, c.-23G>T, and c.-23+1G>A, were reported. Also, ...c.-684_-675del, of uncertain pathogenicity, was found upstream of the basal promoter. We performed a detailed analysis of GJB2 noncoding regions in Portuguese HL patients (previously screened for GJB2 coding mutations and the common GJB6 deletions) and in control subjects, by sequencing the basal promoter and flanking upstream region, exon 1, and 3'UTR. All individuals were genotyped for c.-684_-675del and 14 SNPs. Novel variants (c.-731C>T, c.-26G>T, c.*45G>A, and c.*985A>T) were found in controls. A hearing individual homozygous for c.-684_-675del was for the first time identified, supporting the nonpathogenicity of this deletion. Our data indicate linkage disequilibrium (LD) between SNPs rs55704559 (c.*168A>G) and rs5030700 (c.*931C>T) and suggest the association of c.*168G;*931T allele with HL. The c.*168A>G change, predicted to alter mRNA folding, might be involved in HL.
We have analyzed a single multi-affected breast/ovarian cancer pedigree (BOV3) and have shown consistent inheritance of markers on chromosome 17q with the disease confirming that this family is due ...to the BRCA1 gene. Analysis of 17q haplotypes shows a recombination event in a bilateral breast cancer case which suggests that the BRCA1 gene lies distal to D17S857; D17S857 is thus the new proximal boundary for the region containing BRCA1. Combining this information with previously published mapping information suggests that BRCA1 is contained in a region estimated at 1-1.5 Mb in length. All seven breast tumour/blood pairs examined from this family show loss of heterozygosity in the tumours. The allel retained in each tumour was from the disease-bearing chromosome implicating BRCA1 as a tumour suppressor gene. We have sequenced the 17 beta-oestradiol dehydrogenase genes (EDH17B1 and EDH17B2) which have been suggested as candidate genes for BRCA1 in four members of this family. No germline mutations were detected.
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