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. 2025 Jun 22;135(16):e191008.
doi: 10.1172/JCI191008. eCollection 2025 Aug 15.

Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome

Sadia Saeed  1   2   3 , Anna-Maria Siegert  4 , Y C Loraine Tung  4 , Roohia Khanam  5 , Qasim M Janjua  6 , Jaida Manzoor  6 , Mehdi Derhourhi  1   2 , Bénédicte Toussaint  1   2 , Brian Yh Lam  4 , Sherine Awad Mahmoud  4 , Emmanuel Vaillant  1   2 , Emmanuel Buse Falay  1   2 , Souhila Amanzougarene  1   2 , Hina Ayesha  7 , Waqas I Khan  8 , Nosheen Ramazan  9 , Vladimir Saudek  4 , Stephen O'Rahilly  4 , Anthony P Goldstone  10 , Muhammad Arslan  5 , Amélie Bonnefond  1   2   3 , Philippe Froguel  1   2   3 , Giles Sh Yeo  4
Affiliations

Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome

Sadia Saeed et al. J Clin Invest. .

Abstract

Biallelic variations in SREK1 reduce SNORD115/116 expression, linking severe obesity and Prader-Willi-like traits, offering genetic and molecular insights into a new form of syndromic obesity.

Keywords: Cell biology; Genetics; Molecular genetics; Monogenic diseases; Neuroscience; Obesity.

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Figures

Figure 1
Figure 1. Rare biallelic SREK1 variants lead to downregulation of SNORD115 and SNORD116 and are associated with a syndromic obesity phenotype resembling Prader-Willi syndrome.
(A) Pedigrees of 3 families with SREK1 variants. Affected individuals are shown with shading. M/M and M/N indicate homozygosity and heterozygosity, respectively. (B) SREK1 domain structure and AlphaFold-predicted model highlighting RRMs and EK helices. (C) Volcano plots showing downregulation of SNORD115 and SNORD116 in RRM domain variants. Differential expression analysis of RRM variants versus WT revealed dysregulation of multiple small nucleolar RNAs, particularly in the SNORD115 and SNORD116 families. EdgeR’s quasi-likelihood F-test with a significance threshold of FDR < 0.05. FC, fold change. (D) Quantitative RT-PCR confirmed reduced SNORD115/116 expression in RRM variants versus WT and p.E601K. Multiple unpaired 2-tailed t test. Data indicate the mean ± SEM; *P < 0.05 and **P < 0.01.
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