Additional causal <i>SNRPE</i> mutations in hereditary hypotrichosis simplex
Authors: C. Pan, A. Humbatova, L. Zheng, N. Cesarato, C. Grimm, F. Chen, B. Blaumeiser, A. Catalán‐Lambán, A. Patiño‐García, U. Fischer, R. Cheng, Y. Li, X. Yu, Z. Yao, M. Li, R.C. Betz
Journal: British Journal of Dermatology (2021)

Dear Editor, Hereditary hypotrichosis simplex (HHS) refers to a group of monogenic isolated alopecias characterized by diffuse and progressive loss of scalp and/or body hair. They start in childhood and progress with age. Affected individuals typically present with sparse-to-absent scalp hair, and may have brittle eyebrows and eyelashes, as well as sparse body hair, without any characteristic hair shaft anomalies. HHS research has identified several causal genes.1, 2 In 2012, our group was the first to identify SNRPE as an underlying gene for HHS.3 Since then, no further cases have been reported. However, we now report the identification of further heterozygous mutations in SNRPE (NM_003094) – two novel mutations and one known mutation – in three ethnically diverse cases. This study was approved by the ethics committees of the University Hospital of Bonn, Germany, and Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China. All study procedures were performed in accordance with the principles of the Declaration of Helsinki, and written informed consent was obtained from the respective patient or legal guardian prior to inclusion. The first case concerned a 6-year-old Chinese girl, who presented with sparse scalp hair, and a history of short and brittle eyelashes and eyebrows since birth. Her healthy parents reported that, from the age of 1·5 years, the girl had experienced a pronounced and progressive loss of hair from the scalp, eyebrows and eyelashes. On examination, a paucity of body hair was observed (Figure 1a, left). To determine the underlying genetic cause, multigene panel sequencing was performed for 596 monogenic skin disease genes. A de novo splice site variant c.54+2T>A in SNRPE was identified and confirmed by Sanger sequencing (Figure 1b). The mutation was not identified in 200 control chromosomes of Chinese origin. In vitro hybrid mini-genes were constructed to investigate the splicing effect. This revealed that the mutation activates a new donor splice site in the enhanced green fluorescent protein coding sequence present in the vector and a new acceptor splice site in SNRPE intron 1, resulting in complete skipping of exon 1 and a partial intron 1 (14 base pair) retention. The second case concerned a 2·5-year-old Spanish boy with healthy parents. He had displayed hypotrichosis since birth (Figure 1a, middle). Sanger sequencing of HHS-associated genes revealed the missense variant c.221T>C;p.(Leu74Pro) in SNRPE. This variant is predicted to be pathogenic by the in silico tool MutationTaster (http://www.mutationtaster.org/). The mutation could not be detected in the parents, thus indicating a de novo status. The leucine in position 74 is highly conserved across animal species. According to protein modelling, the proline at the end of a beta strand would affect the adjacent loop. In turn, this would affect the adjacent beta strand, which is part of the interdomain beta leaflet, thus the SmE–SmF interface would be disturbed (Figure 1d). Neither of the novel mutations was present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/) or the 1000 Genomes database (https://www.internationalgenome.org/index.html). The third case concerned a 21-year-old woman of Turkish origin. She presented with sparse hair and absent eyebrows (Figure 1a, right). Exome sequencing analysis and subsequent Sanger sequencing revealed the mutation c.1A>G;p.(Met1?), which affects the start codon of SNRPE. This variant was associated with HHS in our original study.3 The fact that we identified mutations in three ethnically diverse families suggests that mutations in SNRPE are a relatively frequent occurrence. It is thus surprising that no additional cases have been reported since our original publication.3 As also observed in the cases at that time, there was wide phenotypic variation in the present ones. Concerning the splice site mutation, c.54+2T>A directly affects one of the most conserved nucleotides of the 5′ splice site of intron 1. As the newly activated splice site donor, which allows exon 1 skipping, was found in the vector sequence, we cannot exclude the possibility that another mechanism is taking place in vivo. However, if the described aberrant transcript were to be produced, it may be either subjected to RNA decay or, more likely, allow the production of an in-frame 52 amino acid-long protein corresponding to a different small nuclear ribonucleoprotein polypeptide E (SNRPE) isoform (ENST00000367208·1). We suggest that the lower expression of wild-type protein, or the imbalance between the two isoforms, impacts on SNRPE function with respect to hair growth/development.3 Interestingly, a mutation in SNRPE was recently identified in a patient with primary microcephaly and intellectual disability.2 None of the present cases showed either clinical feature. This study identified two novel heterozygous mutations, and one known mutation, in SNRPE. This expands the mutational and ethnic spectrum of HHS. We thank the patients and their families for their cooperation and participation in this study. Chaolan Pan: Conceptualization (equal); Data curation (equal); Investigation (equal); Supervision (equal); Validation (equal); Writing-original draft (equal); Writing-review & editing (equal). Aytaj Humbatova: Data curation (equal); Formal analysis (equal); Investigation (equal); Writing-review & editing (equal). Luyao Zheng: Data curation (equal); Writing-review & editing (equal). Nicole Cesarato: Data curation (equal); Investigation (equal); Visualization (equal); Writing-review & editing (equal). Clemens Grimm: Investigation (equal); Visualization (equal); Writing-review & editing (equal). Fuying Chen: Data curation (equal); Writing-review & editing (equal). Bettina Blaumeiser: Data curation (equal); Writing-review & editing (equal). Ana Catalán-Lambán: Data curation (equal); Investigation (equal); Writing-review & editing (equal). Ana Patiño García : Data curation (equal); Writing-review & editing (equal). Utz Fischer: Visualization (equal); Writing-review & editing (equal). Ruhong Cheng: Data curation (equal); Writing-review & editing (equal). Yue Li: Data curation (equal); Writing-review & editing (equal). Xia Yu: Data curation (equal); Writing-review & editing (equal). Zhirong Yao: Data curation (equal); Writing-review & editing (equal). Ming Li: Conceptualization (equal); Writing-original draft (equal); Writing-review & editing (equal). Regina C. Betz: Conceptualization (equal); Data curation (equal); Funding acquisition (equal); Writing-original draft (equal); Writing-review & editing (equal).