LRIG2 Mutations Cause Urofacial Syndrome

Helen M Stuart ,Blanca Gener,Aslı Kavaz,Andrew Berry,Burcu Bulum,Christian Beetz,Adnan Gücük,Murat Mermerkaya,Fatoş Yalçınkaya,Evren Süer,Berk Burgu,Tarkan Soygür,Ömer Gülpınar,Rita Eva Varga ,Edward A Mckenzie ,Jill Urquhart ,Neil A Hanley ,Wyatt W Yue ,Sarah B Daly ,Sanjeev S Bhaskar ,Malcolm Lewis ,Fırat Erdoğan ,Jonathan E Dickerson ,M Beatriz Orive Olondriz ,Mesrur Selçuk Sılay ,Neil Roberts ,Emma Hilton ,Adrian S Woolf ,Z Bı̇rsı̇n Özçakar ,William G Newman

doi:10.1016/j.ajhg.2012.12.002

Abstract

Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease. We have previously shown that UFS is also caused by mutations in HPSE2, encoding heparanase-2. LRIG2 and heparanase-2 were immunodetected in nerve fascicles growing between muscle bundles within the human fetal bladder, directly implicating both molecules in neural development in the lower urinary tract.

Highlights

Urofacial syndrome (UFS) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying
Autozygosity mapping identified in chromosomal region 1p13.2 a 8.5 Mb segment overlapping that in family 1, and Sanger sequencing of LRIG2 identified homozygous nonsense mutation c.2125C>T (p.Arg709*) in exon 15
Of the 14 families affected by classical UFS, we identified nine (64.3%) with mutations in HPSE2, AluYa5-like insertion (c.1980_1981ins[371], GenBank JX891452) (Biii) were identified

Summary

REPOR T

Autozygosity mapping identified in chromosomal region 1p13.2 a 8.5 Mb segment overlapping that in family 1, and Sanger sequencing of LRIG2 identified homozygous nonsense mutation c.2125C>T (p.Arg709*) in exon 15 This mutation segregated with the disease in the family and was absent from variome databases, 116 local exomes, and 94 healthy Turkish controls. Bladder dysfunction in UFS is similar to that found in Hinman syndrome, or ‘‘non-neurogenic neurogenic bladder.’’17,18 we screened LRIG2 in 23 individuals (13 multiethnic British and 10 previously reported Turkish cases) with Hinman syndrome.[19] Of these, variants in LRIG2 were found in a single individual, a white British male who, at the age of 10 years, presented with a 2 year history of secondary enuresis He was hypertensive and had mild renal impairment. We speculate that the biological pathways mediated by LRIG2 and the heparanases might be implicated in these common disorders of elimination

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