We identified a lineage of rhesus macaques with a frameshift mutation in exon 3 of the BBS7 gene c.160delG (p.Ala54fs) that is predicted to produce a non-functional protein. In humans, mutations in this and other BBS genes cause Bardet-Biedl syndrome, a ciliopathy and a syndromic form of retinitis pigmentosa generally occurring in conjunction with kidney dysfunction, polydactyly, obesity, and/or hypogonadism. Three full- or half-sibling monkeys homozygous for the BBS7 c.160delG variant, at ages 3.5, 4 and 6 years old, displayed a combination of severe photoreceptor degeneration and progressive kidney disease. In vivo retinal imaging revealed features of severe macular degeneration, including absence of photoreceptor layers, degeneration of the retinal pigment epithelium, and retinal vasculature atrophy. Electroretinography in the 3.5-year-old case demonstrated loss of scotopic and photopic a-waves and markedly reduced and delayed b-waves. Histological assessments in the 4- and 6-year-old cases confirmed profound loss of photoreceptors and inner retinal neurons across the posterior retina, with dramatic thinning and disorganization of all cell layers, abundant microglia, absent or displaced RPE cells, and significant gliosis in the subretinal space. Retinal structure, including presence of photoreceptors, was preserved only in the far periphery. Ultrasound imaging of the kidneys revealed deranged architecture, and renal histopathology identified distorted contours with depressed, fibrotic foci and firmly adhered renal capsules; renal failure occurred in the 6-year-old case. Magnetic resonance imaging obtained in one case revealed abnormally low total brain volume and unilateral ventricular enlargement. The one male had abnormally small testes at 4 years of age, but polydactyly and obesity were not observed.
ExperimentName: Naturally occurring BBS7 loss-of-function primate model
NonHumanModel: Rhesus macaque
GeneAlteration: The model animals harbor a naturally occurring homozygous frameshift variant at nucleotide 160 within exon 3 of the BBS7 locus.
ModelPhenotype: HP:0000608 (Macular degeneration), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0000580 (Pigmentary retinopathy), HP:0008046 (Abnormal retinal vascular morphology), progressive kidney disease, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0002171 (Gliosis), HP:0000083 (Renal insufficiency), HP:0012210 (Abnormal renal morphology), HP:0002119 (Ventriculomegaly), HP:0008734 (Decreased testicular size)
HumanPhenotype: HP:0001956 (Truncal obesity), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0001631 (Atrial septal defect), HP:0001640 (Cardiomegaly), HP:0100598 (Pulmonary edema), HP:0012584 (Bilateral renal hypoplasia), HP:0004719 (Hyperechogenic kidneys), HP:0003774 (Stage 5 chronic kidney disease), HP:0000580 (Pigmentary retinopathy), HP:0000648 (Optic atrophy), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007754 (Macular dystrophy)
ModelEvidence: This is a naturally occurring Rhesus macaque model of biallelic BBS7 disruption. The mutant animals exhibit hypoechoic kidney lesions (Figure 1), retinal atrophy with lack of retinal vasculature (Figure 3A), RPE atrophy (Figure 3B), severe atrophy of retinal layers by OCT with greater severity centrally (Figure 3C), retinal gliosis (Figure 3D), Severely reduced amplitudes and delayed time courses of both dark-adapted and light-adapted flicker ERG (Figure 4), reduced brain volume (Figure 5B), dilation of the lateral ventricle (Figure 5A), cystic kidney tubules with loss of nephrons replaced with fibrosis, tubule atrophy, and ectasia (Figure 7), reduced size and histological maturity of testes (Table 1), and vision deficits (Table 1).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring and apparent null variant disrupting BBS7 expression.