Identification and Characterization of Known Biallelic Mutations in the IFT27 (BBS19) Gene in a Novel Family With Bardet-Biedl Syndrome

Schaefer, Eric; Delvallée, Clarisse; Mary, Laura; Geoffroy, Véronique; Marks-Delesalle, Caroline; Holder‐Espinasse, Muriel; Ghoumid, Jamal; Dollfus, Hélène; Muller, Jean

doi:10.3389/fgene.2019.00021

Cited by 29 publications

(22 citation statements)

References 25 publications

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“…Its estimated prevalence in North America and Europe ranges from 1:140 000 to 1:160 000 live births ( 1 ). In the last 20 years, 22 genes have been implicated in BBS ( 2 , 3 ). All of them participate in primary cilia function by coding for proteins involved in the formation of the BBSome ( 4 ), the chaperonin complex ( 5 ), or the basal body, with an essential role in the intraflagellar traffic ( 6 , 7 ).…”

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confidence: 99%

Reproduction Function in Male Patients With Bardet Biedl Syndrome

Koscinski

Mark

Messaddeq

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Purpose Bardet-Biedl syndrome (BBS) is a ciliopathy with a wide spectrum of symptoms due to primary cilia dysfunction including genitourinary developmental anomalies as well as impaired reproduction particularly in males. Primary cilia are known to be required at the following steps of reproduction function: (1) genitourinary organogenesis, (2) in the fetal firing of hypothalamo-pituitary axe, (3) sperm flagellum structure and (4) the first zygotic mitosis conducted by proximal sperm centriole. BBS phenotype is not fully understood. Methods This study explored all steps of reproduction in 11 French male patients with identified BBS mutations. Results BBS patients presented frequently genitourinary malformations as cryptorchidism (5/11), short scrotum (5/8), micropenis (5/8) but unexpectedly, normal testis size (7/8). Ultrasonography highlighted epididymal cysts or agenesis of one seminal vesicle in some cases. Sexual hormones levels were normal in all patients except one. Sperm numeration was normal in 8 out of the 10 obtained samples. Five to 45% of sperm presented a progressive motility. Electronic microscopy did not reveal any homogeneous abnormality. Moreover, a psychological approach pointed a decreased self-confidence linked to blindness and obesity explaining why so few BBS patients express a child wish. Conclusions PC dysfunction in BBS impacts embryology of the male genital tract, especially epididymis, penis and scrotum through an insufficient fetal androgen production. However, in adults, sperm structure does not seem to be impacted. These results should be confirmed in a greater BBS patient cohort, focusing on fertility.

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confidence: 99%

Reproduction Function in Male Patients With Bardet Biedl Syndrome

Koscinski

Mark

Messaddeq

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…We speculate that the RAB28 variant is the cause of PAP in the brothers presented here because RAB28 locates to the cilia like many products of genes associated with PAP, another small GTPase (Rab34) has been shown to be associated with PAP in mice, 18 and, finally, IFT27 (which belongs to the RAB family of genes) is associated with BBS presenting with PAP. 19 We cannot, however, rule out that another recessive gene is causing the PAP, especially as the parents are consanguineous.…”

Section: Discussionmentioning

confidence: 98%

A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium

Jespersgaard

Hey

Ilginis

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Cone-rod dystrophy (CRD) is a rare hereditary eye disorder that causes progressive degeneration of cone and rod photoreceptors. More than 30 genes, including RAB28, have been associated with CRD; however, only a few RAB28 variants have been reported to be associated with CRD. In this study, we describe two brothers with CRD and a homozygous missense variant, c.55G>A (p.Gly19Arg), in RAB28. METHODS. The missense variant was identified as part of a study investigating underlying genetic defects in a large patient cohort (n = 667) using targeted next-generation sequencing of 125 genes associated with retinal dystrophy. Cellular localization of RAB28 and ciliogenesis in patient fibroblasts were investigated by immunofluorescence microscopy. The effect of the missense variant on RAB28 expression level was investigated by quantitative real-time PCR. RESULTS. Two brothers of a consanguineous couple presented with CRD, postaxial polydactyly (PAP), and myopia. Both brothers had a homozygous missense RAB28 variant located in the G1 box of the guanosine triphosphate/guanosine diphosphate binding domain of RAB28. This missense variant caused a considerable reduction of RAB28 localized to the cilia, whereas ciliogenesis seemed unaffected. CONCLUSIONS. The missense variant in RAB28 is classified as likely pathogenic with functional effect on protein localization. The combination of retinal dystrophy and PAP are well known from ciliopathies; however, more data are needed to finally conclude that the RAB28 variant described here is the cause of PAP in these brothers.

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“…Apart from all these, we have defined the atrioventricular canal defect (AVCD), which is a very‐rare anomaly in BBS patients. To date, AVCD has been described in the IFT27 ‐related BBS19 (MIM#615996) syndrome (Schaefer et al., 2019). Interestingly, the IFT27 interacts with BBSome by interacting via LZTFL1 .…”

Section: Discussionmentioning

confidence: 99%

Clinical and exome sequencing findings in seven children with Bardet–Biedl syndrome from Turkey

Gümüş

Tunçez

Öz

et al. 2020

Annals of Human Genetics

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Background Bardet–Biedl syndrome (BBS) is a very‐rare autosomal recessive genetic disorder with severe multisystem manifestations. Genetic testing plays an important role in the early diagnosis of the disease. In this study, while trying to elucidate the genetic etiology of seven individuals with clinical BBS diagnosis from six different families, we also aimed to examine the distribution of BBS variations in this region of Turkey. Methods and materials Exome sequencing analysis is performed for clinically diagnosed patients with BBS in the present study followed by parental segregation. The unreported and previously described clinical features are presented. Results Homozygous variants, four of which are unreported, in BBS‐related genes (BBS5 [c.682‐2A > G], MKKS [c.775del], BBS7 [c.849+1G > T], BBS9 [c.965G > A], BBS10 [c.145C > T], LZTFL1[c.384G > A]) are detected for all the seven individuals included in the study. The most common clinical finding is polydactyly followed by renal anomalies. The clinical features not previously described are correlated to the unreported variant. Conclusions In this study, exome sequencing findings are discussed and four previously unreported disease‐associated variants are described including the fifth BBS‐implicated LZTFL1 change and possible genotype–phenotype correlation is described.

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Identification and Characterization of Known Biallelic Mutations in the IFT27 (BBS19) Gene in a Novel Family With Bardet-Biedl Syndrome

Cited by 29 publications

References 25 publications

Reproduction Function in Male Patients With Bardet Biedl Syndrome

Reproduction Function in Male Patients With Bardet Biedl Syndrome

A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium

Clinical and exome sequencing findings in seven children with Bardet–Biedl syndrome from Turkey

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