Alternative titles; symbols
HGNC Approved Gene Symbol: B9D2
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:41,354,417-41,364,149 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | ?Meckel syndrome 10 | 614175 | Autosomal recessive | 3 |
| Joubert syndrome 34 | 614175 | Autosomal recessive | 3 |
B9D2 belongs to a small family of proteins that also includes B9D1 (614144) and MKS1 (609883), and all 3 B9 domain-containing proteins associate with basal bodies and primary cilia in mammalian cells (Bialas et al., 2009). These proteins localize to the transition zone complex that functions within the cilium (Dowdle et al., 2011).
Using RACE-PCR, Ponsard et al. (2007) cloned B9D2, which they called ICIS1, from human nasal epithelial cell cDNA. The predicted 175-amino acid protein contains a C2 domain and shares significant similarity with EPPB9 (B9D1). Northern blot analysis showed ubiquitous expression of a major 1.0-kb transcript and a minor 2.5-kb transcript in human tissues. ICIS1 orthologs are present in species containing cilia or flagella but are absent in nonciliated species, such as A. thaliana.
Town et al. (2008) cloned mouse B9d2, which they called stumpy. The deduced 175-amino acid protein contains an N-terminal B9/C2 calcium/lipid-binding region. RT-PCR of mouse tissues detected widespread stumpy expression, with highest levels in thymus and skeletal muscle. In situ hybridization showed stumpy expression throughout early postnatal mouse brain.
By searching for genes encoding B9 domain-containing proteins, Bialas et al. (2009) identified B9D2. The deduced protein consists of little more than the approximately 115-amino acid B9 domain. Epitope- or fluorescence-tagged B9D1, B9D2, and MKS1 localized to ciliary axonemes and basal bodies of transfected ciliated mouse IMCD3 cells and to centrosomes of nonciliated IMCD3 cells. In C. elegans, the mks1, mksr1, and mksr2 genes were expressed in the transition zone at the base of sensory cilia, which corresponds to mammalian basal body only. Database analysis revealed orthologs of B9D1, B9D2, and MKS1 in the vast majority of ciliated species, but not in nonciliated organisms. The 3 B9 domain-containing proteins appeared to be evolutionarily ancient, and the duplications resulting in the 3 protein clades preceded speciation.
Ponsard et al. (2007) determined that the B9D2 gene contains 4 exons, the first of which is noncoding.
By genomic sequence analysis, Ponsard et al. (2007) determined that the B9D2 gene is located within the promoter region of the TGFB1 gene (190180) in human, mouse, and rat.
Hartz (2008) mapped the B9D2 gene to chromosome 19q13.2 based on an alignment of the B9D2 sequence (GenBank BC004157) with the genomic sequence (build 36.1).
Bialas et al. (2009) stated that the B9D2 gene maps to chromosome 19q13.2.
Town et al. (2008) mapped the mouse B9d2 gene to chromosome 7.
Using Northern blot analysis, Ponsard et al. (2007) showed that human ICIS1 was differentially expressed during mucociliary differentiation, with expression correlating with the proportion of ciliated cells. Knockdown analysis in Paramecium tetraurelia showed that the Icis1 ortholog was involved with cilia stability or formation.
Town et al. (2008) found that mouse stumpy colocalized with ciliary basal bodies, physically interacted with gamma-tubulin (see TUBG1; 191135), and was present along ciliary axonemes in transfected HeLa cells and canine kidney cells, suggesting that stumpy plays a role in ciliary axoneme extension.
Williams et al. (2011) showed that the conserved proteins Mks1 (609883), Mksr1 (B9D1), Mksr2 (B9D2), Tmem67 (609884), Rpgrip1l (610937), Cc2d2a (612013), Nphp1 (607100), and Nphp4 (607215), functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.
Bialas et al. (2009) found that disruption of Mksr1 or Mksr2 genes via RNA interference in IMCD3 cells reduced the number of ciliated cells compared with control cultures.
Meckel Syndrome 10
In 2 fetuses with Meckel syndrome-10 (MKS10; 614175), Dowdle et al. (2011) identified a homozygous mutation in the B9D2 gene (S101R; 611951.0001). The proband was from a larger cohort of 96 unrelated MKS patients. Immunoprecipitation studies showed that the mutant S101R protein failed to interact with MKS1, although it retained its ability to interact with B9D1. The results indicated that a complex of B9 proteins cooperate to support mammalian ciliogenesis and ciliary protein localization. Disruption of any of the members of this complex can result in Meckel syndrome.
In an Indian fetus with Meckel syndrome, Radhakrishnan et al. (2019) identified homozygosity for a missense mutation in the B9D2 gene (H5Q; 611951.0005) that segregated with disease in the family and was not found in the gnomAD database.
Joubert Syndrome 34
In 2 unrelated patients with Joubert syndrome (JBTS34; see 614175), Bachmann-Gagescu et al. (2015) identified homozygous or compound heterozygous mutations in the B9D2 gene (611951.0002-611951.0004). The mutations were identified by sequencing 27 candidate genes in 428 affected individuals from 363 families by molecular inversion probe targeted capture followed by next-generation sequencing. No functional studies of the variants were performed.
Town et al. (2008) found that conditional loss of stumpy in mouse brain and kidney resulted in perinatal hydrocephalus (see 236600) and severe polycystic kidney disease (see 173900), respectively. Cilia in stumpy mutant brain and kidney cells were absent or markedly deformed, resulting in defective flow of cerebrospinal fluid. Stumpy mutant mice had a deletion of exon 4 of stumpy and exon 1 of the adjacent gene, Tgfb1 (190180), resulting in expression of an in-frame chimeric stumpy/Tgfb1 mRNA. However, Town et al. (2008) demonstrated that stumpy deficiency rather than Tgfb1 disruption caused the phenotype of stumpy mutant mice. They concluded that stumpy is essential for ciliogenesis and suggested that it may be involved in the pathogenesis of congenital hydrocephalus and polycystic kidney disease in humans.
Bialas et al. (2009) disrupted the B9 domain of C. elegans mks1, mksr1, and mksr2. In contrast to the defect found in mouse cells, C. elegans expressing single, double, or triple mks/mksr mutants showed no overt defects in ciliary structure, intraflagellar transport, chemosensation, osmosensation, or lipid accumulation. However, disruption of one B9 domain-containing protein resulted in mislocalization of the others, and all possible double mks/mksr mutant combinations altered insulin signaling, leading to increased life span. The mks1/mksr1/mksr2 triple mutant did not exhibit a longevity phenotype.
Dowdle et al. (2011) found that morpholino suppression of B9d2 in zebrafish resulted in dosage-dependent ciliary phenotypes, including shortened body axes, mediolaterally elongated somites, and notochord imperfections. The defects could be rescued by expression of wildtype human B9D2 mRNA.
In 2 fetuses with Meckel syndrome type 10 (MKS10; 614175) who were born in a consanguineous family from Surinam with an Indian-Pakistani background, Dowdle et al. (2011) identified a homozygous 301A-C transversion in the B9D2 gene, resulting in a ser101-to-arg (S101R) substitution in a highly conserved residue within the B9 domain. The mutation was not detected in 688 control chromosomes. Studies of zebrafish knockouts showed that wildtype human B9D2 could rescue dosage-dependent ciliary defects, whereas the S101R mutant could not, consistent with its being a loss-of-function allele. The mutant allele localized properly to the basal body, but immunoprecipitation studies showed that the mutant S101R protein failed to interact with MKS1 (609883), although it retained its ability to interact with B9D1 (614144). The results indicated that a complex of B9 proteins cooperate to support mammalian ciliogenesis and ciliary protein localization. Disruption of any of the members of this complex can result in Meckel syndrome. The fetuses reported by Dowdle et al. (2011) had occipital encephalocele, postaxial polydactyly of the hands and feet, renal cysts, and hepatic ductal plate malformations; 1 fetus had anencephaly.
In a patient (UW309-3) with Joubert syndrome (JBTS34; see 614175), Bachmann-Gagescu et al. (2015) identified homozygosity for a leu36-to-pro (L36P) substitution in the B9D2 gene. The mutation was identified by sequencing 27 candidate genes in 428 affected individuals from 363 families by molecular inversion probe targeted capture followed by next-generation sequencing. No functional studies of the variant were performed.
In a patient (UW284-3) with Joubert syndrome (JBTS34; see 614175), Bachmann-Gagescu et al. (2015) identified compound heterozygous mutations in the B9D2 gene: gly155-to-ser (G155S) inherited from the mother and pro74-to-ser (P74S; 611951.0004) inherited from the father. The mutation was identified by sequencing 27 candidate genes in 428 affected individuals from 363 families by molecular inversion probe targeted capture followed by next-generation sequencing. No functional studies of the variant were performed.
For discussion of the pro74-to-ser (P74S) mutation in the B9D2 gene that was identified in compound heterozygous state in a patient with Joubert syndrome (JBST34; see 614175) by Bachmann-Gagescu et al. (2015), see 611951.0003.
In an Indian fetus with Meckel syndrome (MKS10; 614175), Radhakrishnan et al. (2019) identified homozygosity for a c.15C-A transversion (c.15C-A, NM_030578.3) in exon 2 of the B9D2 gene, resulting in a his5-to-gln (H5Q) substitution at a highly conserved residue within the functional domain. The parents were heterozygous for the mutation, which was not found in the gnomAD database.
Bachmann-Gagescu, R., Dempsey, J. C., Phelps, I. G., O'Roak, B. J., Knutzen, D. M., Rue, T. C., Ishak, G. E., Isabella, C. R., Gorden, N., Adkins, J., Boyle, E. A., de Lacy, N., and 17 others. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J. Med. Genet. 52: 514-522, 2015. [PubMed: 26092869] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103087]
Bialas, N. J., Inglis, P. N., Li, C., Robinson, J. F., Parker, J. D. K., Healey, M. P., Davis, E. E., Inglis, C. D., Toivonen, T., Cottell, D. C., Blacque, O. E., Quarmby, L. M., Katsanis, N., Leroux, M. R. Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J. Cell Sci. 122: 611-624, 2009. [PubMed: 19208769] [Full Text: https://doi.org/10.1242/jcs.028621]
Dowdle, W. E., Robinson, J. F., Kneist, A., Sirerol-Piquer, M. S., Frints, S. G. M., Corbit, K. C., Zaghloul, N. A., van Lijnschoten, G., Mulders, L., Verver, D. E., Zerres, K., Reed, R. R., Attie-Bitach, T., Johnson, C. A., Garcia-Verdugo, J. M., Katsanis, N., Bergmann, C., Reiter, J. F. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am. J. Hum. Genet. 89: 94-110, 2011. Note: Erratum: Am. J. Hum. Genet. 89: 589 only, 2011. [PubMed: 21763481] [Full Text: https://doi.org/10.1016/j.ajhg.2011.06.003]
Hartz, P. A. Personal Communication. Baltimore, Md. 4/14/2008.
Ponsard, C., Skowron-Zwarg, M., Seltzer, V., Perret, E., Gallinger, J., Fisch, C., Dupuis-Williams, P., Caruso, N., Middendorp, S., Tournier, F. Identification of ICIS-1, a new protein involved in ciliary stability. Front. Biosci. 12: 1661-1669, 2007. [PubMed: 17127412] [Full Text: https://doi.org/10.2741/2178]
Radhakrishnan, P., Nayak, S. S., Shukla, A., Lindstrand, A., Girisha, K. M. Meckel syndrome: clinical and mutation profile in six fetuses. Clin. Genet. 96: 560-565, 2019. [PubMed: 31411728] [Full Text: https://doi.org/10.1111/cge.13623]
Town, T., Breunig, J. J., Sarkisian, M. R., Spilianakis, C., Ayoub, A. E., Liu, X., Ferrandino, A. F., Gallagher, A. R., Li, M. O., Rakic, P., Flavell, R. A. The stumpy gene is required for mammalian ciliogenesis. Proc. Nat. Acad. Sci. 105: 2853-2858, 2008. [PubMed: 18287022] [Full Text: https://doi.org/10.1073/pnas.0712385105]
Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230] [Full Text: https://doi.org/10.1083/jcb.201012116]