ARL6 – Bardet-Biedl syndrome

ARL6 (also known as BBS3) encodes a small GTPase that localizes to the distal end of basal bodies and is essential for ciliary (dis)assembly and Wnt signaling. Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, obesity, renal anomalies, hypogonadism, and learning difficulties. ARL6 was first mapped to the BBS3 locus at 3p13–p12, fulfilling critical linkage and segregation criteria.

Genetic analyses have identified biallelic ARL6 variants in twelve unrelated probands (PMID:36550847, PMID:11050632, PMID:8588586). Segregation has been documented in 19 affected relatives across consanguineous pedigrees and extended Bedouin kindreds (PMID:11050632, PMID:8588586). This accumulation of cases, consistent AR inheritance, and independent linkage studies support a Definitive clinical validity classification.

Multi-family and population studies further reinforce ARL6’s role in BBS. A Newfoundland cohort demonstrated linkage to the BBS3 locus in one kindred among 36 affected individuals (PMID:9888993). An Iranian family with seven affected siblings confirmed assignment to 3p13–p12 (LOD 4.15 at D3S1603) and broadened the phenotypic spectrum with variable polydactyly and obesity (PMID:11050632). Additional mapping in Arab-Bedouin kindreds linked ARL6 to distinct polydactyly and obesity patterns (PMID:8588586).

The ARL6 variant spectrum includes nonsense, frameshift, and splice-site mutations. A recurrent nonsense variant c.528G>A (p.Trp176Ter) was identified in a Japanese boy with progressive night blindness, polydactyly, and obesity (PMID:36550847). Other truncating alleles at codons 43, 76, 88, and 122 have been reported in consanguineous families, highlighting loss-of-function as the predominant mechanism.

Functional evidence is provided by structural and in vivo assays. The crystal structure of GTP-bound ARL6 elucidated pathogenic alterations in nucleotide binding and stability at the ciliary gate (PMID:20207729). Zebrafish knockdown and rescue assays showed that the A89V variant disrupts visual function without affecting general ciliopathy phenotypes, underscoring a tissue-specific role in photoreceptor biology (PMID:21282186).

Integrating genetic and experimental data, ARL6 meets all ClinGen criteria for a Definitive gene-disease association in autosomal recessive Bardet-Biedl syndrome. Loss-of-function ARL6 variants consistently segregate with core and secondary BBS phenotypes, and complementary functional studies validate the mechanistic link to ciliary dysfunction. Key Take-home: ARL6 should be included in diagnostic BBS panels to enable accurate molecular diagnoses and guide genetic counseling.

References

• Medicine • 2022 • A Japanese boy with Bardet-Biedl syndrome caused by a novel homozygous variant in the ARL6 gene who was initially diagnosed with retinitis punctata albescens: A case report. PMID:36550847
• American journal of medical genetics • 2000 • Bardet-Biedl syndrome type 3 in an Iranian family: clinical study and confirmation of disease localization. PMID:11050632
• American journal of medical genetics • 1995 • Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci. PMID:8588586
• Genomics • 1999 • Genetic heterogeneity of Bardet-Biedl syndrome in a distinct Canadian population: evidence for a fifth locus. PMID:9888993
• The Journal of Biological Chemistry • 2010 • Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. PMID:20207729
• Human Molecular Genetics • 2011 • Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. PMID:21282186

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