Triallelic Inheritance in Bardet-Biedl Syndrome, a Mendelian Recessive Disorder

Katsanis, Nicholas; Ansley, Stephen J.; Badano, José L.; Eichers, Erica R.; Lewis, Richard A.; Hoskins, Bethan E.; Scambler, Peter J.; Davidson, William S.; Beales, Philip L.; Lupski, James R.

doi:10.1126/science.1063525

Cited by 581 publications

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“…Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene. This intriguing mechanism has been already postulated for several ciliopathies including Bardet-Biedl syndrome, NPH and even JSRD, [22][23][24][25] and could also help explain the intra-familial variability observed in some INPP5E-mutated families. To this end, the systematic genetic screening of multiple ciliopathy genes based on innovative technologies such as next-generation-sequencing is expected to give a main contribution to clarify the molecular basis underlying the clinical complexity of JSRD and other ciliopathies.…”

Section: Discussionmentioning

confidence: 58%

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

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Section: Discussionmentioning

confidence: 58%

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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“…Both mouse lines had skewed mendelian ratios, with 40-50% embryonic lethality evident by embryonic day 10.5 as partially reabsorbed embryos. Consistent with an oligogenic causality model 18,20 , Bbs1-null and Bbs4-null mice had considerable phenotypic Figure 3 Defects in olfactory protein localization in Bbs1 -/-and Bbs4 -/-mice. Sections of olfactory epithelium were immunostained with antibodies to olfactory cilia-enriched signal transduction components (AC III and G g13 ) and to the dendrite, dendritic knob and cilia protein SLP3.…”

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confidence: 72%

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

et al. 2004

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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...

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“…32 Although traditionally considered an autosomal recessive condition, there are several reported cases of a triallelic mode of inheritance where three mutations in BBS genes are required before the phenotype becomes apparent, or alternatively where a third disease locus acts as a disease modifier. 7,[33][34][35][36] As well as the phenotypic overlaps exhibited between ciliopathies, there is an emerging evidence suggesting that genes mutated in BBS and other ciliopathies exhibit some genetic overlap. 37 For example, mutations in BBS2, BBS4 and BBS6 have been identified in patients with Meckel syndrome.…”

Section: Genetic Basis Of the Diseasementioning

confidence: 99%

“…5,6 Inheritance is traditionally considered autosomal recessive, although notable exceptions exist, whereby BBS may be an oligogenic disorder. 7 The prevalence of BBS varies markedly between populations; from 1:160 000 in northern European populations 5 to 1:13 500 and 1:17 5000, respectively, in isolated communities in Kuwait and Newfoundland, where a higher level of consanguinity prevails. 8,9 Studies on the families in Newfoundland affected with BBS revealed a minimum of six BBS loci and eight different BBS mutations and therefore the high prevalence cannot be attributed to a single founder.…”

Section: Introductionmentioning

confidence: 99%