A novel c.545-546insG mutation in the loricrin gene correlates with a heterogeneous phenotype of loricrin keratoderma.
BACKGROUND
Loricrin keratoderma (LK) is a group of congenital skin abnormalities characterized by the common features of honeycomb palmoplantar keratoderma and diffused ichthyosiform dermatosis. Earlier studies have shown that LK is associated with genetic defects of the loricrin gene.


OBJECTIVE
To determine the correlation between a loricrin mutation and a heterogeneous phenotype of loricrin keratoderma.


METHODS
We obtained DNA samples from a large family in which affected members showed more severe hyperkeratosis on the dorsal parts of their hands, mild palmoplantar keratoderma with no honeycomb-like manifestations and generalized ichthyosis. Screening of the loricrin gene was performed by direct sequencing of the entire coding region. Plasmids encoding the green fluorescent protein-tagged human loricrin were constructed and transferred to 293A cells for subcellular localization analyses.


RESULTS
Molecular analyses of the loricrin gene identified a novel insertion mutation c.545-546insG that resulted in a frameshift after codon 182. This mutation was predicted to produce a mutant protein with a frameshift of its C-terminal sequence of amino acids that embeds a newly generated nuclear localization signal (NLS), and to be 22 amino acids longer than the wild-type protein due to a delayed termination codon. The NLSs appear to result in an accumulation of mutant loricrin within nuclei.


CONCLUSIONS
Our results extend the repertoire of loricrin mutations underlying LK, provide further evidence that heterogeneous phenotypes of LK may be the result of genetic heterogeneity of loricrin mutations, and demonstrate that nuclear accumulation of mutant loricrin is due to the nuclear targeting sequences in the mutant C-terminus.
Peking University Center of Medical Genetics, 38 Xue Yuan Road, Hai-Dian District, Beijing 100083, China.
S
S
Song
C
C
Shen
G
G
Song
X
X
Mao
G
G
Yan
X
X
Wang
M
M
Yan
N
N
Zhong
D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002681:China; D003062:Codon; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010641:Phenotype; D014162:Transfection / Q000379:methods
D003062:Codon; D008565:Membrane Proteins; C064554:loricrin; D049452:Green Fluorescent Proteins