Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 605950

RAS-ASSOCIATED PROTEIN RAB33B; RAB33B

HGNC Approved Gene Symbol: RAB33B

Cytogenetic location: 4q31.1 Genomic coordinates (GRCh38) : 4:139,438,376-139,476,609 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

Small GTP-binding proteins of the RAB family, such as RAB33B, play important roles at defined steps of vesicular transport in protein secretion and the endocytosis pathway (Zheng et al., 1998).

Cloning and Expression

Zheng et al. (1998) cloned and characterized mouse Rab33b, a small GTP-binding protein closely related to RAB33A (300333), especially in the GTP-binding domain. The Rab33b gene encodes a 229-amino acid protein. Unlike mouse and human RAB33A, which have tissue-specific expression, Northern blot analysis indicated that mouse Rab33b is ubiquitously expressed. Using immunofluorescence studies, Zheng et al. (1998) showed that Rab33b is localized to the medial Golgi cisternae, suggesting that it may play a role in intra-Golgi transport.

Gene Structure

Zheng et al. (1998) determined that the mouse Rab33b gene contains 2 exons.

Mapping

Gross (2013) mapped the RAB33B gene to chromosome 4q31.1 based on an alignment of the RAB33B sequence (GenBank AF350420) with the genomic sequence (GRCh37).

Molecular Genetics

By exome sequencing of the proband in a consanguineous Saudi family segregating Smith-McCort syndrome linked to chromosome 4 (SMC2; 615222), Alshammari et al. (2012) identified a homozygous missense mutation in the RAB33B gene (K46Q; 605950.0001). Immunoblot analysis showed severe deficiency of RAB33B in patient cells compared with control cells, and patient fibroblasts also displayed a marked reduction in the immunofluorescence signal corresponding to RAB33B but comparable signal intensity to the Golgi marker giantin (602500).

In a 22-year-old Turkish man with Smith-McCort syndrome-2, who had previously been reported by Neumann et al. (2006), Dupuis et al. (2013) identified a homozygous missense mutation in the RAB33B gene (N148K; 605950.0002). By Western blot analysis and immunofluorescence studies, Dupuis et al. (2013) found marked reduction of the RAB33B protein.

In 3 unrelated patients with Smith-McCort syndrome-2, Salian et al. (2017) identified homozygous or compound heterozygous mutations in the RAB33B gene (605950.0003-605950.0006). The mutations segregated with the disorder in each family.

ALLELIC VARIANTS 6 Selected Examples):

.0001 SMITH-MCCORT DYSPLASIA 2

RAB33B, LYS46GLN
SNP: rs587776958, ClinVar: RCV000043483

By exome sequencing of the proband in a consanguineous Saudi family segregating Smith-McCort syndrome linked to chromosome 4 (SMC2; 615222), Alshammari et al. (2012) identified homozygosity for a c.136A-C transversion in the RAB33B gene, resulting in a lys46-to-gln (K46Q) substitution in the GxxxxGK [S/T] guanine nucleotide-binding domain of the encoded GTPase. Immunoblot analysis showed severe deficiency of RAB33B in patient cells compared with control cells, and patient fibroblasts also displayed a marked reduction in the immunofluorescence signal corresponding to RAB33B but comparable signal intensity to the Golgi marker giantin (602500). The mutation fully segregated with the disease phenotype and was absent on Sanger sequencing of 185 Saudi controls and absent from 160 Saudi exomes.

.0002 SMITH-MCCORT DYSPLASIA 2

RAB33B, ASN148LYS
SNP: rs886044716, ClinVar: RCV000043484

In a 22-year old Turkish man with Smith-McCort dysplasia-2 (SMC2; 615222), who had previously been reported by Neumann et al. (2006), Dupuis et al. (2013) identified a homozygous c.444T-A transversion in exon 2 of the RAB33B gene, predicting an asn148-to-lys (N148K) substitution at a highly conserved residue in the G-4 GTPase domain. By Western blot analysis and immunofluorescence studies, Dupuis et al. (2013) found marked reduction of the RAB33B protein. Both parents were heterozygous for the mutation, which was absent in his unaffected brother and from publicly available databases of known polymorphic variants.

.0003 SMITH-MCCORT DYSPLASIA 2

RAB33B, ARG71TER
SNP: rs1085307128, gnomAD: rs1085307128, ClinVar: RCV000488447

By targeted sequencing of the RAB33B gene in a 7-year-old Indian boy with Smith-McCort dysplasia (SMC2; 615222), who was born of nonconsanguineous parents and did not have a mutation in the DYM gene (607461), Salian et al. (2017) identified homozygosity for a c.211C-T transition (c.211C-T, NM_031296.1) in exon 1, resulting in an arg71-to-ter (R71X) substitution. The mutation segregated with the disorder in the family and was not present in the dbSNP, 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed.

.0004 SMITH-MCCORT DYSPLASIA 2

RAB33B, PHE122SER
SNP: rs1085307129, ClinVar: RCV000488435

By targeted sequencing of the RAB33B gene in a 12-year-old Indian boy with Smith-McCort dysplasia (SMC2; 615222), who was born to consanguineous parents and did not have a mutation in the DYM gene (607461), Salian et al. (2017) identified homozygosity for a c.365T-C transition (c.365T-C, NM_031296.1) in exon 2, resulting in a phe122-to-ser (F122S) substitution at a highly conserved residue. The mutation segregated with the disorder in the family and was not present in the dbSNP, 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed.

.0005 SMITH-MCCORT DYSPLASIA 2

RAB33B, 8-BP DEL, NT48
SNP: rs1085307130, ClinVar: RCV000488443

By targeted sequencing of the RAB33B gene in a 36-year-old man from South Korea with Smith-McCort dysplasia (SMC2; 615222), who did not have a mutation in the DYM gene (607461), Salian et al. (2017) identified compound heterozygous mutations: an 8-bp deletion (c.48delCGGGGCAG, NM_031296.1) in exon 1, resulting in a frameshift and a premature termination codon (Gly17ValfsTer58), and a c.490C-T transition in exon 2, resulting in a gln164-to-ter (Q164X) substitution. The mutations segregated with the disorder in the family and were not present in the dbSNP, 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed.

.0006 SMITH-MCCORT DYSPLASIA 2

RAB33B, GLN164TER
SNP: rs1085307131, ClinVar: RCV000488449

For discussion of the c.490C-T transition (c.490C-T, NM_031296.1) in the RAB33B gene, resulting in a gln164-to-ter (Q164X) substitution, that was found in compound heterozygous state in a patient with Smith-McCort dysplasia-2 (SMC2; 615222) by Salian et al. (2017), see 605950.0005.

REFERENCES

1. Alshammari, M. J., Al-Otaibi, L., Alkuraya, F. S.Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve-Melchior-Clausen locus. J. Med. Genet. 49: 455-461, 2012. [PubMed: 22652534] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100666\]
2. Dupuis, N., Lebon, S., Kumar, M., Drunat, S., Graul-Neumann, L. M., Gressens, P., El Ghouzzi, V.A novel RAB33B mutation in Smith-McCort dysplasia. Hum. Mutat. 34: 283-286, 2013. [PubMed: 23042644] [Full Text: https://doi.org/10.1002/humu.22235\]
3. Gross, M. B.Personal Communication. Baltimore, Md. 5/3/2013.
4. Neumann, L. M., El Ghouzzi, V., Paupe, V., Weber, H.-P., Fastnacht, E., Leenen, A., Lyding, S., Klusmann, A., Mayatepek, E., Pelz, J., Cormier-Daire, V.Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith-McCort dysplasia. Am. J. Med. Genet. 140A: 421-426, 2006. [PubMed: 16470731] [Full Text: https://doi.org/10.1002/ajmg.a.31090\]
5. Salian, S., Cho, T.-J., Phadke, S. R., Gowrishankar, K., Bhavani, G. S., Shukla, A., Jagadeesh, S., Kim, I.-H., Nishimura, G., Girisha, K. M.Additional three patients with Smith-McCort dysplasia due to novel RAB33B mutations. Am. J. Med. Genet. 173A: 588-595, 2017. [PubMed: 28127940] [Full Text: https://doi.org/10.1002/ajmg.a.38064\]
6. Zheng, J. Y., Koda, T., Fujiwara, T., Kishi, M., Ikehara, Y., Kakinuma, M.A novel Rab GTPase, Rab33B, is ubiquitously expressed and localized to the medial Golgi cisternae. J. Cell Sci. 111: 1061-1069, 1998. [PubMed: 9512502] [Full Text: https://doi.org/10.1242/jcs.111.8.1061\]

Contributors:

Michael Muriello - updated : 05/09/2017
Matthew B. Gross - updated : 05/03/2013
Nara Sobreira - updated : 5/3/2013

Creation Date:

Yen-Pei C. Chang : 5/21/2001

Edit History:

carol : 01/05/2018
carol : 05/10/2017
carol : 05/09/2017
mgross : 05/03/2013
carol : 5/3/2013
wwang : 2/4/2010
alopez : 10/18/2002
mgross : 5/21/2001