TBCE – Autosomal Recessive Kenny-Caffey Syndrome

Tubulin-specific chaperone E (TBCE) is a key cofactor for α/β-tubulin folding and microtubule assembly. Biallelic pathogenic variants in TBCE underlie autosomal recessive Kenny-Caffey syndrome (MONDO:0009486), characterized by proportionate short stature, hypoparathyroidism, cortical thickening of long bones, delayed fontanelle closure, and neurodevelopmental impairment.

Genetic evidence is strong. Thirteen affected individuals from five unrelated families carry biallelic TBCE variants in an autosomal recessive inheritance pattern: seven probands homozygous or compound-heterozygous for the splice-site variant c.100+1G>A (PMID:39657131) and six subjects with the missense change c.464T>A (p.Ile155Asn) (PMID:27666369). Segregation of these variants follows Mendelian expectations with unaffected parents as carriers, and no other genetic etiology was identified in each kindred.

The variant spectrum comprises splice-site (c.100+1G>A), missense (c.464T>A (p.Ile155Asn)), nonsense, frameshift, and small indel alleles across TBCE. The recurrent c.100+1G>A allele shows a ~10-fold enrichment in Slavic populations versus gnomAD, consistent with a founder effect and underdiagnosis of milder phenotypes (PMID:39657131).

Functional studies support a hypomorphic loss-of-function mechanism. The c.100+1G>A splice alteration triggers alternative out-of-frame translation, yielding a partially functional TBCE protein with residual tubulin-folding activity in luciferase reporter and Western blot assays (PMID:39657131). In vivo, the mouse pmn mutation (Trp524Gly) recapitulates motor neuron degeneration and microtubule destabilization, both rescued by wild-type TBCE cDNA (PMID:12389029). Similarly, patient fibroblasts with TBCE missense or truncating alleles exhibit decreased polymerized α-tubulin, delayed microtubule re-assembly, and abnormal mitotic spindles (PMID:27666369).

No conflicting evidence has been reported. The combined clinical, genetic, and functional data satisfy ClinGen criteria for a Strong gene–disease association.

Key Take-home: Biallelic TBCE variants cause autosomal recessive Kenny-Caffey syndrome through a hypomorphic loss-of-function mechanism; molecular testing and functional assays are critical for accurate diagnosis and variant interpretation.

References

• The Journal of clinical endocrinology and metabolism • 2024 • Out-of-frame translation rescues a loss-of-function variant in a novel TBCE phenotype. PMID:39657131
• American journal of human genetics • 2016 • TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. PMID:27666369
• Nature genetics • 2002 • A missense mutation in Tbce causes progressive motor neuronopathy in mice. PMID:12389029

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