Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13

Abstract Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2–64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants’ impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition

Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders

Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-beta signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T&amp;gt;G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-beta signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-beta signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund &amp; the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]</p