RAB33B – Smith-McCort Dysplasia

Smith-McCort dysplasia (SMC) is a rare autosomal recessive spondylo-epi-metaphyseal dysplasia characterized by lacy iliac crests, double-humped vertebral bodies, short stature, and normal intelligence. Biallelic variants in RAB33B have been implicated as the second genetic cause of SMC distinct from DYM-related forms (MONDO:0015799).

The first RAB33B pathogenic variant, c.444T>A (p.Asn148Lys), was identified in a second SMC case from a consanguineous family, with Western blot and immunofluorescence showing marked protein reduction (PMID:23042644). Subsequent studies report biallelic RAB33B variants in 6 SMC2 probands from a multicenter cohort (PMID:35477554), 7 individuals from 10 consanguineous families (PMID:38860472), and 3 additional patients with four novel mutations (PMID:28127940), totaling at least 17 probands. Parental testing confirmed autosomal recessive segregation in multiple families.

The variant spectrum in RAB33B includes missense (e.g., c.444T>A (p.Asn148Lys)), nonsense (e.g., c.400C>T (p.Gln134Ter)), frameshift (c.169dup (p.Arg57fs)), and splice-site mutations; no recurrent founder alleles have been described. Segregation of biallelic variants was consistently confirmed by Sanger sequencing in parents and affected sibships.

Clinically, affected individuals display short trunk dwarfism with barrel chest and protruding abdomen, hyperlordosis (HP:0003307), limitation of joint mobility (HP:0001376), and gait disturbance (HP:0001288), while cognitive development remains intact.

Functional assays demonstrate that RAB33B missense variants disrupt Golgi vesicle transport: patient fibroblasts show RAB33B deficiency on immunoblot and mislocalization by immunofluorescence (PMID:22652534). A crystal structure of the Rab33B–Atg16L1 complex revealed that interface mutations abrogate binding and Golgi association, supporting a loss-of-function mechanism (PMID:32737358).

Integration of genetic and experimental data supports a Strong gene–disease association. Additional evidence, including animal models and rescue studies, may further elucidate pathogenesis. Key take-home: RAB33B should be included on diagnostic panels for autosomal recessive skeletal dysplasias given its critical role in Golgi trafficking and bone development.

References

• Human Mutation • 2013 • A novel RAB33B mutation in Smith-McCort dysplasia. PMID:23042644
• Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. • (Journal/year unavailable) PMID:35477554
• American Journal of Medical Genetics Part A • 2024 • Further defining the molecular spectrum and long-term follow-up of 17 patients with Dyggve-Melchior-Clausen and Smith-McCort dysplasia type 2. PMID:38860472
• American Journal of Medical Genetics Part A • 2017 • Additional three patients with Smith-McCort dysplasia due to novel RAB33B mutations. PMID:28127940
• Journal of Medical Genetics • 2012 • Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve--Melchior--Clausen locus. PMID:22652534
• Scientific Reports • 2020 • Crystal structure of the Rab33B/Atg16L1 effector complex. PMID:32737358

Evidence Based Scoring (AI generated)