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Spondylometaphyseal dysplasia, Kozlowski type (SMDK) is an autosomal dominant skeletal dysplasia characterized by short stature, metaphyseal abnormalities, platyspondyly, and variable neurologic features. Radiographically, patients display thickened hyaline cartilage at ossification centers, metaphyseal cupping, and notochordal remnants within vertebrae and discs. Clinical diagnosis is confirmed by identification of pathogenic variants in TRPV4, which encodes a calcium-permeable cation channel. TRPV4 and Spondylometaphyseal Dysplasia, Kozlowski type have a well-established gene-disease relationship.
Multiple independent case reports have described heterozygous missense variants in TRPV4 in SMDK probands. A de novo c.2389G>A (p.Glu797Lys) was identified in a 9-year-old male with progressive kyphoscoliosis and compressive myelopathy (PMID:38721578). A c.1781G>A (p.Arg594His) substitution was reported in a 2-year-old patient with typical metaphyseal changes and notochordal remnants (PMID:28687525). In a cohort of 20 SMDK probands, 19 carried TRPV4 mutations, including a recurrent R594H hotspot in 12 subjects and seven novel alleles (PMID:20577006). An additional nine unrelated SMDK patients from 21 families all harbored heterozygous TRPV4 variants, underscoring replication across multiple centers (PMID:21658220).
Although formal segregation counts are limited, the recurrent R594H allele in unrelated families and de novo occurrence of p.Glu797Lys support pathogenicity. No large multi-generation pedigrees with detailed co-segregation have been published, but heterozygous alleles consistently track with disease in simplex and familial cases.
The variant spectrum in SMDK is dominated by missense substitutions clustered in cytoplasmic and pore-lining domains. Recurrent codon 594 substitutions (c.1781G>A (p.Arg594His)) and exon 15 variants such as c.2389G>A (p.Glu797Lys) illustrate hotspots. All reported SMDK alleles are single nucleotide changes predicting amino acid substitutions; loss-of-function and splice variants have not been linked to this phenotype.
Functional studies demonstrate a gain-of-function mechanism concordant with human phenotype. Disruption of the L596–W733 bond (e.g., p.Leu596Pro) elevates basal open probability and reduces agonist responsiveness, leading to constitutive channel activation (PMID:25737550). Moreover, mutations adjacent to the calmodulin binding domain (p.Glu797Lys) abolish CaM-mediated autoinhibition, further increasing constitutive Ca2+ influx (PMID:26170305). These data are consistent across electrophysiological and biophysical assays.
Collectively, over 30 unrelated SMDK probands, including de novo occurrences and multiple recurrent alleles, combined with robust gain-of-function evidence, firmly establish TRPV4 as a strong gene-disease association. Key take-home: TRPV4 gain-of-function missense variants should be considered diagnostic for SMDK in patients with characteristic radiographic features.
Gene–Disease AssociationStrong~30 probands across multiple unrelated families with replication and de novo events; consistent phenotype–genotype correlation and functional data Genetic EvidenceStrong30 affected individuals including 2 de novo variants and recurrent Arg594 hotspot across independent cohorts ([PMID:28687525]; [PMID:38721578]; [PMID:20577006]; [PMID:21658220]) Functional EvidenceModerateIn vitro electrophysiology and structural studies show gain-of-function via disrupted TRPV4 gating and loss of autoinhibition ([PMID:25737550]; [PMID:26170305]) |