Congenital ichthyosis: mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis

Abstract

Background: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood. Methods: To investigate genotype-phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI. Results: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin. Discussion: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…160 The ultrastructural features of the so-called EM classification described by the Heidelberg group are based on a glutaraldehyde fixation of the skin biopsy specimen. [206][207][208][209][210] With this technique polygonal clefts in the SC can be observed as an ultrastructural key feature of TGase-1 deficiency, 211 aberrant vesicular structures may indicate NIPAL4 (;ICHTHYIN ) mutations in ARCI, 33 and trilamellar membrane aggregations in the SC and SG (EM type IV) are pathognomonic for ichthyosis prematurity syndrome. 89 Detachment of the SC from the SG with asymmetric cleavage of corneodesmosomes is a specific feature of NS.…”

Molecular identification of ancient and modern mammalian magnesium transporters

“…There is evidence that human ichthyin and its Drosophila ortholog spichthyin are also localized to early recycling endosomes and the plasma membrane (20,169). The peripheral localization of the NIPA proteins suggests that they might play a role, such as mediation of Mg 2ϩ transport, at the surface membrane.…”

Inherited ichthyoses/generalized Mendelian disorders of cornification

“…42,43,[62][63][64] In contrast, aberrant vesicular structures indicate NIPA-like domain containing 4 (also known as ichthyin) mutations in ARCI. 65 Furthermore, trilamellar membrane aggregations in the stratum corneum and stratum granulosum are …”