Transmembrane protein 53 craniotubular dysplasia (OMIM # 619727): The skeletal disease and consequent blindness of this new disorder.

Craniotubular dysplasia, Ikegawa type (OMIM #619727) denotes the autosomal recessive skeletal disease identified in 2021 featuring blindness acquired in childhood. Five young members of four Indian families harbored a homozygous indel within TMEM53 (OMIM *619722), the gene that encodes transmembrane protein 53 (TMEM53). When intact, TMEM53 spans the nuclear envelope of osteoprogenitor cells, dampens BMP-SMAD signaling, and thereby slows bone formation. Consequently, defective TMEM53 accelerates osteogenesis. Herein, an American boy is compound heterozygous for a novel deletion and a novel missense mutation within TMEM53. His vision and sensorineural hearing became impaired. Radiographic survey revealed diploic thickening of his skull, broad calvarial and facial bones, skeletal modeling errors, vertebral body flattening, wide ribs, and osteopenia of expanded bones. DXA areal bone density (gm/cm2) Z-scores were low. His optic, auditory, and spinal canals were narrow. Mineral metabolism was intact. Serum alkaline phosphatase and osteocalcin levels were normal yet CTX was high. Iliac crest histomorphometry documented accelerated bone formation. His acute vision loss briefly improved following prednisone administration, optic canal decompression, and optic nerve sheath fenestration, but then progressed despite further surgeries and zoledronate treatment aimed to suppress bone turnover. Next generation sequencing of genes associated with elevated skeletal mass, including from high bone turnover, did not suggest an etiology. Whole genome sequencing then revealed within TMEM53: i) a paternally transmitted 54-base deletion, which included the mRNA splice acceptor site for exon 2 as well as 31 bases of exonic sequence (c. 62-23_92del), and ii) a maternally transmitted missense variant (c.650C > T, p.Ser217Leu: NM_024587.4/NP_078863.2) which is extremely rare in gnomAD (frequency = 0.000036), replaces Ser217 highly conserved across species, and is scored as damaging by SIFT and Mutation Taster. We call this new osteopathy TMEM53 craniotubular dysplasia.

Vacuolar occupancy is crucial for cell elongation and growth regardless of the underlying mechanism.

In the physiological range, the phytohormone auxin inhibits the growth of underground tissues. In the roots of Arabidopsis thaliana, cell size inhibition has been shown to be accompanied by auxin-mediated reduction of vacuole size. A tonoplast-localized protein family (Networked 4) with actin-binding capacity was demonstrated to modulate the compactness of the vacuole. Overexpression of NET4A led to smaller, more spherical and compact vacuoles, which occupied less cellular space compared to wild type. This reduction of vacuolar occupancy is similar to the observed auxin-induced decrease in occupancy, albeit there are enormous morphological differences. Here, we show that a net4a net4b double mutant and a NET4A overexpressor line are still sensitive to auxin-induced vacuolar constrictions. However, the overexpressor showed a partial auxin resistance accompanied by more compact vacuoles, thereby indicating an additional regulatory mechanism. Furthermore, we show that other NET superfamily members do not compensate for the loss of NET4A and NET4B expression on the transcriptional level. This leads us to hypothesize that regulation of vacuole size is a general mechanism to regulate cell expansion and that other players besides NET4 must participate in regulating the vacuole-cytoskeleton interface.