ORPHA: 99885;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.5 | Diabetes mellitus, permanent neonatal 4 | 618858 | Autosomal dominant; Autosomal recessive | 3 | INS | 176730 |
A number sign (#) is used with this entry because of evidence that permanent neonatal diabetes mellitus-4 (PNDM4) is caused by heterozygous or homozygous mutation in the INS (176730) gene on chromosome 11p15.
Permanent neonatal diabetes mellitus-4 (PNDM4) is characterized by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life (summary by Polak et al., 2008).
For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (606176).
Stoy et al. (2007) reported that PNDM patients with mutations in the INS gene presented at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, did not have beta-cell autoantibodies, and were treated from diagnosis with insulin. C-peptide values where measured were very low or undetectable, with all values less than 200 pmol/liter.
Edghill et al. (2008) reported that the median age at diagnosis of PNDM for INS mutation carriers was 11 weeks, and patients presented with either symptomatic hyperglycemia (41%) or diabetic ketoacidosis (59%). All patients were treated with insulin replacement therapy. Autoantibodies, when measured, were not detected. Birth weights were reduced (median, 2.7 kg, corresponding to the sixth percentile), consistent with in utero growth retardation due to reduced insulin secretion.
Polak et al. (2008) stated that PNDM patients with INS mutations had a later presentation of diabetes and no associated symptoms, compared to patients with K(ATP) channel, i.e., KCNJ11 (600937) or ABCC8 (600509), mutations.
Colombo et al. (2008) noted that 9 of 11 patients with permanent diabetes diagnosed in early life (age 37 days to 4 years) studied showed near-normal weight at birth, a finding clearly different from the low birth weight in patients with KCNJ11 mutations; they suggested that the beta-cell insufficiency in patients with INS mutations may occur primarily after birth, and noted that the observed postpartum decline in C-peptide was consistent with the hypothesis that a postnatal failure to maintain beta-cell mass due to proteotoxic proinsulin misfolding is a primary cause of PNDM in these patients.
Carmody et al. (2015) studied a male infant, born to first-cousin Southeast Asian parents, who had severe hyperglycemia at birth and required subcutaneous insulin thereafter, who also displayed a structurally normal pancreas on ultrasound but had undetectable C-peptide.
Stoy et al. (2007) studied a family in which neonatal diabetes segregated as an autosomal dominant trait and affected family members were negative for mutation in the KCNJ11 (600937) and ABCC8 (600509) genes. Linkage analysis led to the identification of INS on chromosome 11p15 as a candidate gene.
In 2 of the families studied by Colombo et al. (2008), the transmission pattern of PNDM4 was consistent with autosomal dominant inheritance; in other cases de novo occurrence was demonstrated. The transmission pattern of PNDM4 in the family studied by Carmody et al. (2015) was consistent with autosomal recessive inheritance.
In affected members of a 3-generation family with autosomal dominant neonatal diabetes, who did not have mutations in the KCNJ11 and ABCC8 genes, Stoy et al. (2007) identified heterozygosity for a missense mutation in the INS gene (176730.0008). The authors then sequenced the INS gene in 83 probands with PNDM without a known genetic cause and identified 9 additional heterozygous missense mutations in the INS gene in 15 families (see, e.g., 176730.0009-176730.0011).
Edghill et al. (2008) screened the INS gene in a series of 1,044 patients with permanent diabetes diagnosed during infancy, childhood, and adulthood and identified 16 different heterozygous INS mutations in 35 PNDM probands (see, e.g., 176730.0010-176730.0013), 12 of whom had been previously reported by Stoy et al. (2007).
Polak et al. (2008) analyzed the INS gene in 38 patients with PNDM and 1 with nonautoimmune early-infancy diabetes who were negative for mutations in the GCK (138079), KCNJ11, and ABCC8 genes, and identified heterozygosity for 3 different missense mutations in critical regions of the preproinsulin molecule (see 176730.0010-176730.0012) in 4 probands with marked variability in age of diagnosis and disease progression. The authors stated that in their cohort, INS mutations represented approximately 10% of all PNDM cases,
In 9 probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (600937), Colombo et al. (2008) identified heterozygosity for 7 different mutations in the INS gene (see, e.g., 176730.0010). Expression of the mutant proinsulins in HEK93 cells demonstrated defects in insulin protein folding and secretion.
In a male infant with PNDM4, born of consanguineous Southeast Asian parents, who was negative by whole-exome and Sanger sequencing for mutation in 36 known monogenic diabetes-associated genes, including INS, Carmody et al. (2015) detected homozygosity for a deep intronic INS variant (176730.0017) by examination of low-coverage intronic regions. The mutation was present in heterozygosity in his parents and 1 brother, none of whom had diabetes, although his mother had required insulin to treat gestational diabetes in all 3 of her pregnancies. In addition, the proband's maternal grandmother, who was heterozygous for the mutation, developed insulin-requiring diabetes mellitus at age 45, and a maternal aunt and uncle, for whom DNA was not available, were diagnosed with insulin-requiring diabetes mellitus at 28 and 36 years of age, respectively. The nondiabetic paternal grandmother also carried the mutation. Noting that 20 to 30% of neonatal monogenic diabetes cases have no known etiology, the authors suggested that mutations within deep noncoding regions might be the cause.
Colombo et al. (2008) proposed that, because individuals with INS gene mutations may present with diabetes well beyond 6 months of age and cannot be distinguished from patients with type 1 diabetes except for the absence of type 1 diabetes autoantibodies, the term PNDM should be replaced with 'monogenic diabetes of infancy (MDI),' a broad definition including any form of diabetes, permanent or transient, with onset during the first years of life and caused by a single gene defect.
Carmody, D., Park, S.-Y., Ye, H., Perrone, M. E., Alkorta-Aranburu, G., Highland, H. M., Hanis, C. L., Philipson, L. H., Bell, G. I., Greeley, S. A. W. Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism. J. Med. Genet. 52: 612-616, 2015. [PubMed: 26101329] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103220]
Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., and 8 others. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J. Clin. Invest. 118: 2148-2156, 2008. [PubMed: 18451997] [Full Text: https://doi.org/10.1172/JCI33777]
Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 57: 1034-1042, 2008. [PubMed: 18162506] [Full Text: https://doi.org/10.2337/db07-1405]
Polak, M., Dechaume, A., Cave, H., Nimri, R., Crosnier, H., Sulmont, V., de Kerdanet, M., Scharfmann, R., Lebenthal, Y., Froguel, P., Vaxillaire, M. Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. Diabetes 57: 1115-1119, 2008. [PubMed: 18171712] [Full Text: https://doi.org/10.2337/db07-1358]
Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc. Nat. Acad. Sci. 104: 15040-15044, 2007. [PubMed: 17855560] [Full Text: https://doi.org/10.1073/pnas.0707291104]