ESPE Abstracts (2018) 89 RFC2.6

The Novel R211Q POP1 Homozygous Mutation Causes Severe Short Stature But Uniquely Only Subtle Skeletal Dysplasia

Maha Abdulhadi-Atwana,b, Tehila Klopshtockc, Muna Sharafd, Ariella Weinberg-Shokrunc, Ephrat Levy-Lahadc & David Zangend

aPalestine Red Crescent Society Hospital, Hebron, Palestine; bBethlehem Arab Society for Rehabilitation, Beit Jala, Palestine; cShare Zedek Medical Center, Jerusalem, Israel; dHadassah Hebrew University Medical Center, Jerusalem, Israel

Background: Processing of Precursor 1 (POP1) is a core protein component of the Ribonuclease-Mitochondrial RNA Processing (RNase-MRP) enzymatic complex, an essential complex in all eukaryotes. Mutations in RMRP, encoding the RNA moiety of the complex cause cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders, characterized by severe disproportionate short stature. Recently, five patients harboring mutations in POP1 have been reported with anauxetic dysplasia (spondylo-epi-metaphyseal dysplasia with extremely short stature) involving the spine, and long bones’ epiphyses and metaphyses in all these cases.

Patients & Methods: A 6y old boy, born to consanguineous parents, presented with severe short stature (height 90.5 cm, SDS −5.68). Physical exam revealed mild legs shortness (US:LS ratio is 1.15:1) and mild brachydactyly. A male sibling (20y) and a female cousin (25y) are extremely short (138 and 135 cm, respectively), with no apparent skeletal deformities. Skeletal survey and whole exome sequencing were performed for the proband. Relative abundance of the RMRP RNA and unprocessed pre5.8s rRNA (a substrate of RNase-MRP complex) were measured in affected siblings, non-affected parents and control.

Results: Skeletal survey exemplified relatively short forearm, mild shortness of metacarpals, subtle widening and irregularity of metaphyseal borders of long bones and delayed bone age by 2.5 years. There was no epiphyseal involvement, and no skeletal abnormalities in cranium, vertebral bodies or pelvis. Using exome sequencing the proband, his affected brother and cousin were found to be homozygous for the R211Q novel mutation in POP1 gene. Parents and healthy siblings were all heterozygous. The arginine residue at position 211 is highly evolutionarily conserved. The RNA moiety of the RNase-MRP complex quantified in RNA extracted from peripheral lymphocytes was dramatically reduced (20 times less) in affected patients compared to non-affected parents, sibling and control. Pre5.8s rRNA was not increased in patients’ RNA. 3-dimentional complex modeling of the mutation to explain the relative subtle pathophysiology is underway.

Conclusions: This study identified a novel homozygous POP1 mutation in three patients causing a unique phenotype of skeletal dysplasia. Unlike the few previously reported cases, the skeletal dysplastic changes are subtle and merely metaphyseal. Gene expression assays indicate dramatically reduced RMRP RNA levels but no elevation in pre5.8s rRNA levels possibly explaining the uniquely mild phenotype. POP1 mutations should be considered in familial cases with severe short stature even when skeletal dysplasia is not strongly evident.

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