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The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope.

ABSTRACT: The erythrokeratodermas (EKs) are a group of disorders characterized by erythematous plaques associated with variable features that include palmoplantar keratoderma. One type of EK is known as "progressive symmetric erythrokeratoderma" (PSEK). We studied members of a family of Japanese origin in which the index case with PSEK had had well-demarcated nonmigratory erythematous plaques on her extremities since birth. Sequence determination of the loricrin gene revealed an insertion of a C following nucleotide 709. The mutation results in a frameshift that changes the terminal 91 amino acids in the wild-type polypeptide into missense amino acids and adds 65 additional residues. This further implicates loricrin defects in the pathogenesis of disorders with palmoplantar keratoderma and pseudoainhum.

SUBMITTER: Ishida-Yamamoto A

PROVIDER: S-EPMC1715943 | biostudies-other | 1997 Sep

REPOSITORIES: biostudies-other

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The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope.

Ishida-Yamamoto A A McGrath J A JA Lam H H Iizuka H H Friedman R A RA Christiano A M AM

American journal of human genetics 19970901 3

The erythrokeratodermas (EKs) are a group of disorders characterized by erythematous plaques associated with variable features that include palmoplantar keratoderma. One type of EK is known as "progressive symmetric erythrokeratoderma" (PSEK). We studied members of a family of Japanese origin in which the index case with PSEK had had well-demarcated nonmigratory erythematous plaques on her extremities since birth. Sequence determination of the loricrin gene revealed an insertion of a C following ...[more]

PMID: 9326323

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Project description:Abstract Introduction: Progressive osseous heteroplasia (POH) is a rare bone disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. Whereas 60-70% of the POH patients have paternally inherited inactivating mutations in GNAS gene, the remaining 30-40% harbor no specific etiologies. FAM111B gene mutations, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a rare autosomal dominant disorder with high frequency of de novo missense mutations, which are believed to cause extensive fibrosis and adiposis of many tissues, though the exact mechanism is unknown. To our knowledge there are no reports of FAM111B associated with POH. Case: We describe a 15-year-old African American boy who presented with generalized calcific nodules, contractures, and muscle weakness leading to immobility, beginning at the age of 6 years. Cutaneous exam showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs showed extensive heterotopic ossification involving soft tissues and muscles surrounding the bilateral humeri, ulnae, femurs, and bilateral tibias/fibulas. Computed tomography of the chest, abdomen, and pelvis showed extensive muscle ossifications involving right latissimus dorsi, left scalene, bilateral pectoralis and external oblique abdominal, right iliacus, bilateral gluteal, left adductor, and left hamstring. There was also an involvement of the subcutaneous tissues of the right upper back and left lower quadrant of the abdomen, left posterior sacral region, bilateral hips, and the fascia superficial to the erector spinae muscles with no abnormal ossifications in the bones. The clinical and radiographic findings were consistent with POH. Whole Exome Sequencing revealed a de novo heterozygous frameshift mutation in FAM111B (OMIM # 615584) of c.1462delT (p.Cys488Valfs*21) variant, causing replacement of C-terminal region with 21 alternative amino acids. Multiple previously reported disease-associated variants appear to localize within the same domain, supporting the functional importance of this region, though none have been previously associated with POH. Thus, we consider this variant to be pathogenic. Conclusion: This is the first case of POH caused by a mutation in FAM111B gene. Whether POH phenotype could be explained by mutations in FAM111B gene traditionally reserved for POIKTMP remains unclear. Further evaluations are necessary to fully elucidate this finding and potential mechanism by which the FAM111B gene mutation contributes to POH.

Project description:Purpose: To identify genes and molecular mechanisms associated with disease progression during (7 weeks of age) and after (16 weeks) the peak of photoreceptor death in dogs affected with XLPRA2, a canine model of early-onset XLRP caused by a microdeletion in RPGR exon ORF15. Methods: Expression profiles of diseased and normal dog retinas at both ages were compared using a canine retinal custom cDNA microarray. Data normalization and filtering were performed with GeneSpring, statistical analysis with Significance Analysis of Microarrays. Real-time PCR using Taqman probes, western blot and immunohistochemistry (IHC) were applied on selected genes to confirm and expand the microarray results. Results: At 7 and 16 weeks, respectively, 56 and 18 transcripts were down-regulated in mutant retinas compared to normals. None of the transcripts was differentially expressed (DE) at both ages, suggesting the involvement of temporally distinct molecular pathways. Down-regulated genes included PAX6, CHML, and RDH11 at 7 weeks and CRX and SAG at 16 weeks, which are necessary for visual system development and function. Genes directly or indirectly active in apoptotic processes were altered at 7 weeks (CAMK2G, NTRK2, PRKCB, RALA, RBBP6, RNF41, SEPT5, SMYD3, SPP1, and TUBB2C) and 16 weeks (SLC25A5 and NKAP). Furthermore, DE genes at 7 weeks (ELOVL6, GLOD4, NDUFS4, and REEP1) and 16 weeks (SLC25A5 and TARS2) are related to mitochondrial functions. Real-time PCR of 11 genes confirmed the microarray results and showed differential expression for additional genes not on the array, such as GFAP, RHO, OPN1SW, CNGB3 and the mutated RPGR. Western blotting and IHC analysis also confirmed the high reliability of the presented transcriptomic data. Conclusions: A list of mutated genes in RPGRORF15 diseased retinas, which are likely candidates to further study their role in age-related photoreceptor degeneration diseases, is reported at different crucial ages. The results indicate that at 7 weeks a combination of non-classical anti- and pro-apoptotic genes appears to be involved in photoreceptor degeneration, whereas at both 7 and 16 weeks expression of mitochondria related genes indicates they may play a relevant role in the disease process.

Dataset Information

The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope.

Publications

The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope.

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