Case report: A de novo RASopathy-causing SHOC2 variant in a Chinese girl with noonan syndrome-like with loose anagen hair

Abstract

Pathogenic variants in the RASopathy-causing SHOC2 gene have been suggested to cause Noonan syndrome-like with loose anagen hair (NS/LAH). This condition is characterized by facial features resembling Noonan syndrome (NS), short stature, growth hormone deficiency (GHD), cognitive deficits, cardiac defects, and ectodermal abnormalities, including easily pluckable, sparse, thin, slow-growing hair, hyperpigmented skin and hypernasal voice. The mutation spectrum of SHOC2 is narrow, and only 8 pathogenic variants have been identified. Here, we report a 5-year-3-month-old Chinese female who displays characteristics typical of NS and has normal neurodevelopment. Trio-based whole-exome sequencing (WES) revealed a de novo variant (c.1231A>G, p.Thr411Ala) in SHOC2. This variant has been recently reported in one subject in the literature who displayed facial features typical of NS and also presented with significant speech delays, moderate intellectual disabilities, epilepsy, bilateral sensorineural deafness and renal dysplasia. The differential phenotypes between these subjects deserve to be further investigated. Next, we reviewed the clinical pictures of NS/LAH and noticed that a recurrent SHOC2 Ser2Gly variant was more likely to result in delayed neurodevelopment and short stature, compared to other SHOC2 variants. And growth hormone (GH) therapy could improve height prognosis. It was noticed that the slight sleep problems and friendly and relatively mature personality observed in our patient may be a novel phenotype of NS/LAH. Our study reconfirms the pathogenic nature of the SHOC2 Thr411Ala variant. It also provides insights into the genotype-phenotype relationship in NS/LAH and a foundation for its genetic counseling, diagnosis and treatment.

Structural insights into the role of SHOC2‐MRAS‐PP1C complex in RAF activation

“…The structure of the SMP complex reveals that the NS mutations observed in the SMP complex interfaces either increase van der Waal contacts (SHOC2-M173I/V, SHOC2-M173I_L174F or SHOC2-Q269H_H270Y), form a de novo hydrogen bond (SHOC2-Q269R and PP1CB-P49R) or relieve charge-charge repulsion (PP1CB-E183A) or steric hindrance (SHOC2-T411A). Interestingly, the methyl group of SHOC2-T411 was noted by Kwon et al to be destabilizing towards SMP complex formation, before its recent identification in two NS patients where it was found to be mutated (T411A) to relieve this steric hindrance [37,38,49]. The role of the NS mutation, SHOC2-G53R, remains unclear as this region of SHOC2 is in the intrinsically disordered region which is not resolved in any of the structures.…”

“…Multiple germline mutations in SHOC2, MRAS and PP1CB proteins have been detected in Noonan syndrome (NS) and Noonan-like syndrome with anagen hair (NSLH or Mazzanti syndrome), types of RASopathy disorders (Fig. 1A) [37][38][39][40][41][42][43][44][45][46][47]. To explore the structural and functional role of SHOC2 and MRAS in the recruitment of PP1C to the plasma membrane and the dephosphorylation of the CR2-pS in RAF kinases, four research groups, including us, recently determined the structure of the SMP complex by cryo-EM and X-ray crystallography [22,[48][49][50].…”

“…The most common NS mutation in SHOC2 is the S2G mutation, which constitutively targets all cellular SHOC2 to the plasma membrane through the creation of a de novo N-myristoylation site [47]. However, several other NS mutations, such as G53R, M173I/V, Q269R, T411A and two double mutations M173I_L174F and Q269H_H270Y are observed in SHOC2 [37,38,46]. Currently, all seven NS mutations observed in PP1C are only seen in the PP1CB isoform of PP1C [43][44][45][55][56][57].…”

“…Interestingly, the methyl group of SHOC2‐T411 was noted by Kwon et al . to be destabilizing towards SMP complex formation, before its recent identification in two NS patients where it was found to be mutated (T411A) to relieve this steric hindrance [37,38,49]. The role of the NS mutation, SHOC2‐G53R, remains unclear as this region of SHOC2 is in the intrinsically disordered region which is not resolved in any of the structures.…”