SPINK5 – Netherton Syndrome

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis characterized by the triad of congenital ichthyosiform erythroderma, bamboo hair (trichorrhexis invaginata), and atopic diathesis. NS is caused by biallelic loss-of-function mutations in SPINK5, which encodes the serine protease inhibitor LEKTI, essential for epidermal barrier integrity and immune regulation ([PMID:10835624]).

Genetic evidence for SPINK5–NS is definitive. Initial studies described 11 distinct SPINK5 mutations in 13 families, all predicting premature termination codons and cosegregating with disease ([PMID:10835624]). A larger series in 21 families identified 18 additional mutations—including nonsense, frameshift, and splice-site defects—in probands and affected relatives, confirming autosomal recessive inheritance and variant segregation ([PMID:11841556]). A recurrent homozygous mononucleotide deletion c.153del (p.Gln52LysfsTer6) has been used for prenatal diagnosis in multiple consanguineous kindreds ([PMID:11857617]).

The variant spectrum in NS is broad: more than 75 unique mutations have been reported, clustered in exons encoding LEKTI domains critical for protease inhibition. Recurrent founder alleles (e.g., c.1431-12G>A in Greece, c.652C>T in Finland) and population-specific variants underscore the importance of targeted screening in at-risk groups ([PMID:22089833], [PMID:26865388]).

Functional studies demonstrate that LEKTI deficiency leads to unopposed kallikrein hyperactivity, premature degradation of corneodesmosomal cadherins, and skin barrier disruption. Spink5 knockout mice recapitulate NS skin pathology with increased stratum corneum trypsin- and chymotrypsin-like activities and corneocyte detachment ([PMID:16628198]). Immunohistochemistry of patient skin reveals absent LEKTI and aberrant expression of protease substrates and barrier proteins ([PMID:15304086]).

Genotype–phenotype analyses reveal that N-terminal truncations of LEKTI are associated with more severe neonatal presentations and failure to thrive, whereas C-terminal or splicing variants with residual LEKTI expression correlate with milder phenotypes ([PMID:22377713]). Deep intronic and synonymous mutations altering splicing further expand the molecular spectrum and explain variable clinical expressivity.

Molecular confirmation of SPINK5 mutations supports accurate diagnosis, enables prenatal and carrier testing, and informs genetic counseling. Functional insights into protease dysregulation offer avenues for targeted therapeutic development. Key take-home: SPINK5 mutation analysis is essential for definitive diagnosis and management of Netherton syndrome.

References

• Nature Genetics • 2000 • Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome PMID:10835624
• The Journal of Investigative Dermatology • 2002 • Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families PMID:11841556
• The Journal of Dermatology • 2006 • Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome PMID:16628198
• The Journal of Investigative Dermatology • 2004 • SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases PMID:15304086
• Prenatal Diagnosis • 2002 • Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis PMID:11857617
• Journal of Human Genetics • 2012 • A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements PMID:22377713

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