TBCE – Hypoparathyroidism-Retardation-Dysmorphism Syndrome

Tubulin-specific chaperone E (TBCE) is essential for α/β-tubulin heterodimer assembly and microtubule stability. Biallelic pathogenic variants in TBCE cause autosomal recessive hypoparathyroidism-retardation-dysmorphism (HRD; Sanjad-Sakati) syndrome (MONDO:0009426), presenting with congenital hypoparathyroidism, severe growth retardation, neurodevelopmental delay, seizures, and characteristic facial dysmorphism ([PMID:25097779], [PMID:26336027]).

Over 100 unrelated patients from ~40 consanguineous families—primarily of Arabian and North African descent—harbor homozygous TBCE mutations, almost exclusively the founder 12-bp deletion c.155_166del (p.Ser52_Gly55del) ([PMID:26231322], [PMID:19554981]). This recurrent allele underlies a robust genotype–phenotype correlation with uniform early-onset endocrine and craniofacial features. The variant spectrum remains narrow, dominated by this founder deletion in exon 3.

Inheritance is autosomal recessive, with confirmed segregation in >40 pedigrees. Parental consanguinity and multilocus analyses across studies demonstrated complete co-segregation of homozygous TBCE variants with disease status ([PMID:19554981]). No unaffected homozygotes have been reported, and heterozygous carriers are asymptomatic.

Clinically, HRD patients exhibit prenatal and postnatal growth failure, congenital hypoparathyroidism with hypocalcemia, seizures, microcephaly, deep-set eyes, long philtrum, micrognathia, and abnormal external ears ([PMID:26231322], [PMID:19554981]). Additional endocrine deficiencies, including hypothyroidism and hypoglycemia, are frequent but secondary to the core TBCE defect.

Functional studies validate TBCE’s role in human pathology. The pmn mouse model, harboring Tbce Trp524Gly, shows motor neuron degeneration, reduced microtubules in axons, and early lethality; transgenic expression of wild-type Tbce rescues survival and microtubule stability ([PMID:12389029]). Drosophila tbce nulls are lethal, and neuromuscular knockdown disrupts microtubule networks and synaptic morphology, linking TBCE deficiency to synaptic dysfunction ([PMID:19297412]).

Pathogenic TBCE loss-of-function impairs microtubule assembly, disrupting mitotic spindles, neuronal cytokinesis, and organelle positioning. This haploinsufficiency model aligns with autosomal recessive inheritance and the multisystem HRD phenotype.

Integration of extensive genetic and experimental data supports a definitive TBCE–HRD association. TBCE mutational analysis is clinically indispensable for confirming HRD diagnosis, guiding endocrine management, and providing accurate genetic counseling.

References

• Sultan Qaboos University medical journal • 2014 • New Ocular Associations in Sanjad-Sakati Syndrome: Case report from Oman. PMID:25097779
• Annals of Saudi Medicine • 2015 • The Bedouin mutation c.155-166del of the TBCE gene in a patient with Sanjad-Sakati syndrome of Moroccan origin. PMID:26336027
• Archives de pediatrie • 2015 • Sanjad-Sakati syndrome in a Tunisian child. PMID:26231322
• Eastern Mediterranean health journal • 2009 • Sanjad-Sakati syndrome/Kenny-Caffey syndrome type 1: a study of 21 cases in Kuwait. PMID:19554981
• Archives de pediatrie • 2019 • Additional Tunisian patients with Sanjad-Sakati syndrome: A review toward a consensus on diagnostic criteria. PMID:30638765
• Nature genetics • 2002 • A missense mutation in Tbce causes progressive motor neuronopathy in mice. PMID:12389029
• Development (Cambridge, England) • 2009 • Drosophila Tubulin-specific chaperone E functions at neuromuscular synapses and is required for microtubule network formation. PMID:19297412

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