Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34-amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.

Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.

Congenital cataracts (CCs) are clinically and genetically heterogeneous. Mutations in the same gene may lead to CCs differing in inheritance, morphology and severity. Loci for autosomal dominant posterior polar CC and total CC have both been mapped to the chromosomal 1p36 region harboring the EPHA2 receptor tyrosine kinase gene. Here, we report mutations of EPHA2 in three CC families from different ancestral groups. In a Chinese family with posterior polar CC, we identified a missense mutation, c.2819C>T (p.T940I), replacing a critical amino acid that functions at the receptor oligomerization interface. In a British family with posterior polar CC and an Australian family with total CC, we found a frameshift mutation (c.2915_2916delTG) and a splicing mutation (c.2826-9G>A), respectively. These two mutations are predicted to produce novel C-terminal polypeptides with 39 identical amino acids. Yeast two-hybrid analysis showed stronger interaction between the total CC-associated mutant EPHA2 and low molecular weight protein-tyrosine phosphatase, a negative regulator of EPHA2 signaling. Our results implicate the Eph-ephrin signaling system in development of human cataract and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCs.

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PurposeAlthough the mental health status of doctoral students deserves attention, few scholars have paid attention to factors related to their mental health problems. We aimed to investigate the prevalence of depression and anxiety in doctoral students and examine possible associated factors. We further aimed to assess whether mentoring relationships mediate the association between research self-efficacy and depression/anxiety.MethodsA cross-sectional study was conducted among 325 doctoral students in a medical university. The Patient Health Questionnaire 9 and Generalized Anxiety Disorder 7 scale were used to assess depression and anxiety. The Research Self-Efficacy Scale was used to measure perceived ability to fulfill various research-related activities. The Advisory Working Alliance Inventory-student version was used to assess mentoring relationships. Linear hierarchical regression analyses were performed to determine if any factors were significantly associated with depression and anxiety. Asymptotic and resampling methods were used to examine whether mentoring played a mediating role.ResultsApproximately 23.7% of participants showed signs of depression, and 20.0% showed signs of anxiety. Grade in school was associated with the degree of depression. The frequency of meeting with a mentor, difficulty in doctoral article publication, and difficulty in balancing work–family–doctoral program was associated with both the level of depression and anxiety. Moreover, research self-efficacy and mentoring relationships had negative relationships with levels of depression and anxiety. We also found that mentoring relationships mediated the correlation between research self-efficacy and depression/anxiety.ConclusionThe findings suggest that educational experts should pay close attention to the mental health of doctoral students. Active strategies and interventions that promote research self-efficacy and mentoring relationships might be beneficial in preventing or reducing depression and anxiety.