Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse

Abstract

Defects in cilia are associated with several human disorders, including Kartagener syndrome 1 , polycystic kidney disease 2,3 , nephronophthisis 4 and hydrocephalus 5 . We proposed that the pleiotropic phenotype of Bardet-Biedl syndrome (BBS), which encompasses retinal degeneration, truncal obesity, renal and limb malformations and developmental delay, is due to dysfunction of basal bodies and cilia 6,7 . Here we show that individuals with BBS have partial or complete anosmia. To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, we examined mice with deletions of Bbs1 or Bbs4. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement.BBS is caused by mutations in at least eight loci, seven of which have been identified 6,[8][9][10][11][12][13][14] . Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 . In addition, all known orthologs of the mammalian BBS proteins are expressed specifically in ciliated sensory neurons in Caenorhabditis elegans 6,10 , raising the possibility that disruption of these proteins will lead to ciliary defects.Although the capacity to generate cilia is shared by most mammalian cells, some cells develop specialized cilia that mediate sensory function. The olfactory receptor neuron is a highly specialized example of a ciliated cell in which the apical process terminates in a complex structure, the dendritic knob, containing multiple basal bodies 15 . Eight or more immotile cilia emanate from this dendritic knob and extend more than 60 mm into the mucus. Given that at least three BBS proteins localize to the olfactory epithelium 6,7 , we considered that if ciliary defects underlie BBS, then olfactory structure and sensory function should be compromised in individuals with BBS. To test this hypothesis, we evaluated 19 individuals with BBS from 14 unrelated families using the fully validated, 12-item smell identification test. To compensate for varying degrees of visual impairment in subjects, each test was administered in a controlled setting by the same personnel. The test has a maximum possible score of 12. We compared the score of each individual with sex-derived normative data, ranked the relative degree of olfactory function by percentile and categorized olfactory function as normal (score of 9-12), abnormal (score of 8) or Ten individuals, including all three o15 y of age, scored in the normal range (9-12). Two subjects were abnormal (score of 8), and seven scored in th...

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

“…The phenotypes of the MKKS-knockout mouse (Fath et al, 2005) closely resemble those of mice disrupted for the BBS1, BBS2, or BBS4 genes (Kulaga et al, 2004;Nishimura et al, 2004), and many of these phenotypes have been suggested to be caused by ciliary dysfunction. In the case of the BBS2-knockout mouse, the photoreceptor degeneration is preceded by mislocalization of rhodopsin, which indicates a defect in protein transport.…”

Cilium-generated signaling and cilia-related disorders

“…Since obesity and several of the other phenotypes that accompany BBS are common, studying this disorder potentially will yield new insights into the cellular and molecular mechanisms that underlie these important phenotypes. That several of the disease phenotypes (retinal dystrophy, situs inversus, and anosmia) already were linked to cilia suggested a connection between BBS and cilia, and several recent studies have confirmed this idea [94][95][96][97] (reviewed in Mykytyn and Sheffield 98 ). The BBS1 and BBS4 gene products are essential for formation of normal cilia in mouse olfactory epithelium.…”

Bardet–Biedl syndrome

“…In a study of 19 BBS patients, nine had anosmia/ hyposmia. 25 Many affected individuals suffer from a degree of clumsiness and 40% of one cohort describe signs of ataxia and poor coordination. 4 Dysdiadochokinesia and past pointing are common (79%) as are difficulties with tandem walking and the Fogg test.…”