Diabetes mellitus has a clear aetiology and well-known characteristics. There are currently eight major types of diabetes, including type A insulin resistance syndrome (U.S. National Library of Medicine Genetics Home Reference, 2019), Donohue syndrome (also known as leprechaunism) (Huggard et al., 2015), Rabson–Mendenhall syndrome (Musso et al., 2004), and lipoatrophic diabetes (Lawson, 2009). The present study investigated a 32-year-old patient with a rare POC1A gene mutation resulting in a type of diabetes mellitus, for which a detailed clinical diagnosis and molecular biological analysis were performed.

Blood glucose, insulin, and related antibody tests were performed after admission. The results showed mild liver function damage, normal thyroid function, a normal routine blood test, a fasting blood glucose of 15.02 mmol/L, and glycosylated haemoglobin of 12.5%. The patient’s urine glucose was 4+ and negative for diabetes autoantibodies (ICA, IAA, GADA). Colour Doppler ultrasound showed a fatty liver. The patient’s insulin and connecting peptide (C-peptide) release test results are shown in Figure 3.

The patient had significantly elevated blood glucose but did not rely on insulin therapy and did not have signs of ketoacidosis. He was negative for insulin-related antibodies and was found to have high C-peptide and insulin levels during the inpatient examination, so type 1 diabetes was excluded. The patient was treated with a high dose of insulin and was judged to be insulin resistant on the basis of the results of his insulin and C-peptide release tests. Based on the patient’s short stature, facial features, and parental consanguinity history, a particular type of diabetes needed to be considered for diagnosis, and gene sequencing was performed. A total of 3 mL of whole peripheral blood was extracted from three members of the family (the proband, his father, and his mother) for trio whole-exome sequencing. The results showed that the patient had a pathogenic POC1A (NM_015426.5) gene variation; specifically, the base at position 241 in the coding region was a cytosine-to-thymine (C-to-T) mutation, and this nonsense mutation was located in exon 3. As a result, the encoded protein was terminated in advance at amino acid 81, shortening the 327 amino acids (c.241(exon 3) C>T, p.R81X,327) (see Figure 4).The associated diseases were short stature, nail hypoplasia, facial dysmorphism, hypotrichosis, all of which are associated with SOFT syndrome (clinically characterised by diabetes, short stature, and phalangeal abnormalities in the fingers). And the phalanges we detected in this study of both hands were thick and short. In combination with the patient’s clinical features, the diagnosis of a specific type of diabetes mellitus (SOFT syndrome) was confirmed. The proband was homozygous, and his parents were heterozygous, which is consistent with the pathogenesis of autosomal recessive disorders.

There are many substitution–nonsense mutations in the POC1A gene has been reported before (Sjöblom et al., 2006; Cancer Genome Atlas Network, 2012; George et al., 2015; Landau et al., 2015; Robinson et al., 2015; Hayward et al., 2017; Newell et al., 2019; Lawson et al., 2020). In the COSMIC database, 267 variants are reported in this gene, the mutation in this case, in c.241C>T, p.R81* COSM4716289; is also reported in three samples, and another variant of this also reported in c.242G>A; p.R81Q, COSM3775216 in one sample. In 2012, Shalev et al. (Shalev et al., 2012) first reported an autosomal recessive disorder caused by mutations in the PCO1A gene that was characterised by short stature, nail hypoplasia, facial dysmorphism, and hypotrichosis. Subsequently, Sarig (Sarig et al., 2012) reported such cases and applied the term ‘SOFT syndrome’. To date, 29 cases of SOFT syndrome have been reported worldwide, with only one case being reported in China (Li et al., 2021). According to current reports, patients with SOFT syndrome present with various manifestations, including macrocephaly, microcephaly, low-set ears, hypertrichosis, hyperlipidaemia, acanthosis nigricans, and severe insulin resistance, in addition to the more common features (Al-Kindi et al., 2020).

Most patients diagnosed with SOFT syndrome have acanthosis nigricans and severe insulin resistance, but they are usually diagnosed with dwarfism rather than diabetes before puberty, at which stage their glycaemic values have not yet reached the criteria for diabetes mellitus. In the present study, a 32-year-old male patient was initially diagnosed with type 2 diabetes mellitus and primary dwarfism. Due to the patient’s facial features, thinning hair, severe insulin resistance, and parents’ consanguineous marriage, the possibility of a genetic mutation was put forward. The results of subsequent genetic testing confirmed a pathogenic mutation at the POC1A G81 gene locus.

Centrioles are important structures found in most animal cells. They consist of nine highly stable microtubule triads that form a barrel-shaped blade about 500 nm long and 200 nm in diameter (Azimzadeh and Marshall, 2010). Centrioles are thought to play an essential role in human mitosis and cilia formation, which are associated with human diseases, especially developmental abnormalities. The proteome of centrioles 1 (POC1) is a core component of centrioles and includes two different isoforms, POC1A and POC1B, which are encoded by different genes. POC1 is mainly involved in centriole replication and length control, as well as ciliogenesis (Venoux et al., 2013). POC1A is localised on the inner wall of centrioles, is proximal to them, and plays a role in centriole formation and maintenance (Venoux et al., 2013). Mutations in POC1A can lead to abnormal mitotic spindles and centrioles, which severely impair centriole function and cause disease (Shaheen et al., 2012). Spermatogonial stem cell transplantation studies have shown that POC1A is essential for the normal function of Sertoli cells and germ cells and that POC1A mutations can lead to skeletal dysplasia and primary dwarfism (Geister et al., 2015).

Most of the currently reported POC1A gene mutations in SOFT syndrome occur in exons 6, 8, 9, and 10. Three of these cases, all of which exhibit short stature, hyperlipidaemia, acanthosis nigricans, and extreme insulin resistance with highly overlapping clinical features, have been found to have homozygous frameshift mutations in exon 10 of the POC1A gene (Azimzadeh and Marshall, 2010). Thus, Giorgio (Azimzadeh and Marshall, 2010) suggested that POC1A gene mutations can lead to two different conditions: SOFT syndrome and variant POC1A (vPOC1A) syndrome. The primary clinical differences between these two phenotypes are extreme dyslipidaemia with insulin resistance and acanthosis nigricans, which are the main features of vPOC1A syndrome but do not appear in SOFT syndrome. A novel homozygous frameshift mutation in the patient’s POC1A may affect two of the three protein products of this gene, which are associated with excess centrioles and multipolar mitotic spindles in primary cells with extreme dyslipidaemia and insulin resistance (Majore et al., 2021). POC1A encodes a protein associated with centrioles throughout the cell cycle and is involved in the mitotic spindle and primary cilia function; its dysfunction leads to extreme dyslipidaemia and insulin resistance (Majore et al., 2021).

The mutation in the POC1A gene, c.241C>T, is not consistent with any previously reported cases. However, only one case of gene variation at this locus has been identified, and further studies are needed to explore its specific pathogenesis. A timely and accurate genetic diagnosis of such patients with specific clinical manifestations of diabetes would help clinicians select appropriate treatments and predict and prevent the development of the disease in family members.