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. 2023 Jul;60(7):712-716.
doi: 10.1136/jmg-2022-108946. Epub 2022 Dec 21.

Craniosynostosis, inner ear, and renal anomalies in a child with complete loss of SPRY1 (sprouty homolog 1) function

Rebecca S Tooze #  1 , Eduardo Calpena #  1 , Stephen R F Twigg  1 , Felice D'Arco  2 ; Genomics England Research Consortium; Emma L Wakeling  3 , Andrew O M Wilkie  4
Collaborators, Affiliations

Craniosynostosis, inner ear, and renal anomalies in a child with complete loss of SPRY1 (sprouty homolog 1) function

Rebecca S Tooze et al. J Med Genet. 2023 Jul.

Abstract

Introduction: SPRY1 encodes protein sprouty homolog 1 (Spry-1), a negative regulator of receptor tyrosine kinase signalling. Null mutant mice display kidney/urinary tract abnormalities and altered size of the skull; complete loss-of-function of Spry-1 in humans has not been reported.

Methods: Analysis of whole-genome sequencing data from individuals with craniosynostosis enrolled in the 100,000 Genomes Project identified a likely pathogenic variant within SPRY1. Reverse-transcriptase PCR and western blot analysis were used to investigate the effect of the variant on SPRY1 mRNA and protein, in lymphoblastoid cell lines from the patient and both parents.

Results: A nonsense variant in SPRY1, encoding p.(Leu27*), was confirmed to be heterozygous in the unaffected parents and homozygous in the child. The child's phenotype, which included sagittal craniosynostosis, subcutaneous cystic lesions overlying the lambdoid sutures, hearing loss associated with bilateral cochlear and vestibular dysplasia and a unilateral renal cyst, overlapped the features reported in Spry1-/- null mice. Functional studies supported escape from nonsense-mediated decay, but western blot analysis demonstrated complete absence of full-length protein in the affected child and a marked reduction in both parents.

Conclusion: This is the first report of complete loss of Spry-1 function in humans, associated with abnormalities of the cranial sutures, inner ear, and kidneys.

Keywords: genetics; human genetics; musculoskeletal diseases.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Clinical features of proband II-1 homozygous for SPRY1 nonsense variant. (A–C) Photographs of the index patient aged 11 weeks showing scaphocephaly, turricephaly, bitemporal narrowing, hypertelorism, earlobe creases, cystic lesions overlying the lambdoid suture (B, arrow) and deep palmar crease (C). (D–F) Axial maximum intensity projection three-dimensional high-resolution T2-weighted images aged 8 months. (D–E) On his right side, he displays cochlear hypoplasia type 4 (arrows) with reasonably normal semi-circular canals. On the left, he has an incomplete partition type 1 cochlea (arrowhead), dilated vestibule with dysplastic lateral semi-circular canals. (F) Sagittal T1-weighted images showing small corpus callosum with hypoplastic splenium (double arrows).
Figure 2
Figure 2
Identification of SPRY1 nonsense variant and effect on expression of RNA and protein. (A) Dideoxy sequencing traces for each member of the pedigree. The arrow indicates the position of the c.80T>A nonsense variant in SPRY1. (B) RT-PCR of SPRY1 including three unaffected controls (C1-3), the mother (I-2), father (I-1) and proband (II-1). (C) Western blot analysis using an antibody against Spry-1, targeting an epitope downstream of the stop-gain; lanes are labelled as in part B. The blots were stripped and reprobed using an antibody against GAPDH as a positive control.
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