Novel insights into diabetes mellitus due to DNAJC3 ‐ defect: Evolution of neurological and endocrine phenotype in the pediatric age group

Abstract

Background: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58 IPK) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. Objective: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. Methods: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. Results: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. Conclusion: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation

“…Of particular note most recently, two unrelated individuals presenting with a very similar phenotype to our siblings, that included hyperinsulinaemic hypoglycaemia, were found to be homozygous for different mutations at the same splice site c.393+2 T>G and c.393+2T>C (Ozon et al, 2020). These mutations are predicted to cause exon skipping and loss of protein function (Table 1).…”

GWAS Hits for Bilateral Convergent Strabismus with Exophthalmos in Holstein Cattle Using Imputed Sequence Level Genotypes

“…Finally, approximately 2 Mb downstream of the association signal on chromosome 12, the DnaJ heat shock protein family (Hsp40) member C3 ( DNAJC3 ) gene is located. This gene has been mainly implicated in the development of diabetes [ 37 , 38 ], but also neurodegeneration [ 37 ]. The pathomechanism of diabetes caused by DNAJC3 mutations further involves mitochondrial degeneration [ 39 ].…”

Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex

“…Mutant variants of BiP interaction partners are associated with the manifestation of neurological diseases [ 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 , 304 , 305 ]. In 2005, recessive SIL1 mutations were linked to the phenotypical manifestation of Marinesco–Sjögren syndrome (MSS; MIM: 248800) ( Figure 8 ), a rare autosomal recessively inherited multisystemic disorder characterized by a vacuolar myopathy, congenital or infantile manifesting cataracts and cerebellar atrophy leading to ataxia ( Figure 8 b) [ 276 , 277 ].…”

“…In vivo studies utilizing the “woozy” mouse model revealed that decrease of ERj6 ameliorates ER stress and neurodegeneration in these animals suggesting that alterations in the nucleotide exchange reaction of BiP cause ER stress and neurodegeneration in Sil1-deficient neurons [ 278 , 279 ]. In 2014, recessive DNAJC3 mutations were linked to Diabetes mellitus complicated by multisystemic neurodegeneration including ataxia, upper-motor-neuron damage, peripheral neuropathy, sensorineural hearing loss, and cerebral atrophy [ 261 ] (MIM: 616192) and a further clinical and molecular genetic study confirmed the phenotype associated with recessive loss of function mutations within DNAJC3 [ 292 ]. Although precise molecular data unravelling the underlying pathomechanisms are still scarce a recent study points at BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis [ 292 ].…”