Jacob Prince, Lindelöf Hillevi, Rustad Cecilie F, Sutton Vernon Reid, Moosa Shahida, Udupa Prajna, Hammarsjö Anna, Bhavani Gandham SriLakshmi, Batkovskyte Dominyka, Tveten Kristian, Dalal Ashwin, Horemuzova Eva, Nordgren Ann, Tham Emma, Shah Hitesh, Merckoll Else, Orellana Laura, Nishimura Gen, Girisha Katta M, Grigelioniene Giedre
Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
NPJ Genom Med. 2023 Nov 22;8(1):39. doi: 10.1038/s41525-023-00380-x.
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.
核糖体蛋白L13相关的脊椎骨骺发育不良伴严重身材矮小（SEMD-RPL13，MIM#618728）是一种罕见的常染色体显性疾病，其特征为身材矮小和骨骼改变，如主要影响下肢的轻度脊椎和骨骺发育不良。2019年，勒凯涅克等人首次报道了其遗传病因，迄今为止，已在编码核糖体蛋白RPL13（NM_000977.3）的基因中鉴定出6个致病变体。本研究展示了来自7个无亲缘关系家庭的12名年龄在2至64岁之间的受影响个体的临床和影像学数据，显示出高度可变的表现。受影响个体的身材矮小程度从轻度到重度不等，保留了相同的脊椎和骨骺发育不良的影像学模式，但髋部和膝部畸形的严重程度各不相同。鉴定出两个新的错义变体，即c.548 G>A，p.(Arg183His)和c.569 G>T，p.(Arg190Leu)，以及一个先前已知的剪接变体c.477+1G>A，证实了在一个高度特异性的RNA结合基序中存在突变聚集。对这些变体对蛋白质影响的结构分析和解释表明，通过mRNA结合破坏该蛋白质的核糖体外功能可能在SEMD-RPL13的骨骼表型中起作用。此外，我们还展示了该疾病的性腺和体细胞嵌合现象。
