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Abstract
Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone dystrophy. The mutation was also found in two of the proband's siblings with retinal dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of retinal dystrophy, including those caused by mutations in the tubby-like protein TULP-1, loss of function of TUB in the proband and two affected family members was associated with early-onset obesity, consistent with an additional role for TUB in energy homeostasis.
Highlights
Inherited retinal dystrophies are a major cause of childhood blindness
Retinitis pigmentosa (RP) describes a genetically heterogeneous group of disorders characterized by night blindness, early peripheral visual field loss, and subsequent loss of central vision, leading to severe visual impairment
We screened TUB using Sanger sequencing in 96 additional probands with childhood-onset autosomal-recessive RP, where previous genetic investigations had not identified the causative gene, and in 55 patients with severe obesity and a variety of ocular phenotypes from the Genetics of Obesity Study (GOOS); no additional potentially pathogenic variants were found
Summary
Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs∗9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. Disease-associated mutations involving other TUB family members have not been identified to date in humans.
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