Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi–like syndrome
Sadia Saeed, Anna-Maria Siegert, Y.C. Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y.H. Lam, Sherine Awad Mahmoud, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas I. Khan, Nosheen Ramazan, Vladimir Saudek, Stephen O’Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo
Sadia Saeed, Anna-Maria Siegert, Y.C. Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y.H. Lam, Sherine Awad Mahmoud, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas I. Khan, Nosheen Ramazan, Vladimir Saudek, Stephen O’Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo
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Research Letter Cell biology Genetics Neuroscience

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

Abstract

Authors

Sadia Saeed, Anna-Maria Siegert, Y.C. Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y.H. Lam, Sherine Awad Mahmoud, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas I. Khan, Nosheen Ramazan, Vladimir Saudek, Stephen O’Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo

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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.

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Rare biallelic SREK1 variants lead to downregulation of SNORD115 and SNO...
(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.