TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.

A Trimer Consisting of the Tubulin-specific Chaperone D (TBCD), Regulatory GTPase ARL2, and β-Tubulin Is Required for Maintaining the Microtubule Network

“…The TBCD mutants that had reduced binding to ␤-tubulin showed an increase in the rate of tubulin polymerization compared with control cells. Similar studies have recently added to our appreciation of the importance of TBCD and its binding to ARL2 and ␤-tubulin in related neurological syndromes (18,19,20,39). Together, these findings argue that the TBCD⅐ARL2⅐␤-tubulin complex is vital for the proper homeostasis that is required in microtubule dynamics and human health.…”

“…As a consequence, we propose the TBCD⅐ARL2⅐␤-tubulin complex to be a key player in the folding process and potentially separately in regulating the lifetime or stability of the microtubule array. Finally, the studies by Flex et al (17) and others (18,19,20,39) highlight the clinical significance of the TBCD⅐ARL2⅐␤-tubulin trimer and suggest that continued study of this complex will prove to be beneficial to both the scientific and clinical communities.…”

A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course

“…Altogether, 21 different TBCD variants have been reported, including three splice variants, one nonsense variant, and 17 missense variants [9][10][11][12][13]. The missense variants affect amino acids located in different parts of TBCD, and are generally predicted to interfere with folding of α solenoid repeats, loop structures, and/or interactions with other molecules, thus affecting protein conformation and function.…”

“…To our knowledge, only 24 patients with TBCD variants, originating from 15 families, have been described at present [9][10][11][12][13]. These patients had a similar age at onset (median 5 months), but considerably longer survival (Fig.…”

“…It is thought that microtubule dynamics and function as well as cell-typespecific effects are involved in disease-specific pathogenesis [5,7,8]. More recently, variants in the tubulin-specific cofactor D (TBCD) have been identified in a series of patients with early-onset, progressive encephalopathy, extending the spectrum of microtubule-related neurodegenerative disease [9][10][11][12][13].…”