Faculty Collaboration Database

A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. J Clin Endocrinol Metab 2014 Oct;99(10):E2117-22

Date

07/25/2014

Pubmed ID

25057881

Pubmed Central ID

PMC4184067

DOI

10.1210/jc.2014-1949

Scopus ID

2-s2.0-84907662133 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

CONTEXT: CDKN1C, a cyclin-dependent kinase inhibitor and negative regulator of cellular proliferation, is paternally imprinted and has been shown to regulate β-cell proliferation. CDKN1C mutations are associated with growth disorders, including Beckwith-Wiedemann syndrome and IMAGe syndrome.

OBJECTIVE: To investigate the genetic basis for a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.

DESIGN, SETTING, AND PARTICIPANTS: Genomic DNA samples (15 affected and 26 unaffected from a six-generation pedigree) were analyzed by genome-wide single nucleotide polymorphism arrays, whole exome and Sanger sequencing, and multiplex ligation-dependent probe amplification.

MAIN OUTCOME MEASURE(S): Subjects were assessed for height, weight, adrenal gland size, ACTH, diabetes status, and testis volume. Linkage and sequence analyses were performed, and the identified genetic variant was functionally evaluated in reconstitution studies.

RESULTS: The pedigree followed a paternally imprinted pattern of inheritance, and genetic linkage analysis identified a single significant 2.6-megabase locus on chromosome 11p15, within the imprinting center region 2. Multiplex ligation-dependent probe amplification did not detect copy number variants or methylation abnormalities. Whole exome sequencing revealed a single novel variant in the proliferating cell nuclear antigen-binding region of CDKN1C (c.842G>T, p.R281I) that co-segregated with affected status and, unlike variants found in IMAGe, did not entirely abrogate proliferating cell nuclear antigen binding. Clinical assessments revealed that affected individuals had low testicular volume but normal adrenal function.

CONCLUSIONS: We report a novel CDKN1C mutation associated with features of IMAGe syndrome, but without adrenal insufficiency or metaphyseal dysplasia, and characterized by early-adulthood-onset diabetes. Our data expand the range of phenotypes observed with CDKN1C defects and suggest that CDKN1C mutations may represent a novel monogenic form of diabetes.

Author List

Kerns SL, Guevara-Aguirre J, Andrew S, Geng J, Guevara C, Guevara-Aguirre M, Guo M, Oddoux C, Shen Y, Zurita A, Rosenfeld RG, Ostrer H, Hwa V, Dauber A

Author

Sarah L. Kerns PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adrenal Glands
Adrenal Insufficiency
Adrenocorticotropic Hormone
Adult
Age of Onset
Beckwith-Wiedemann Syndrome
Body Height
Body Weight
Cyclin-Dependent Kinase Inhibitor p57
Diabetes Mellitus, Type 2
Female
Fetal Growth Retardation
Genetic Linkage
Genetic Variation
Genome-Wide Association Study
Humans
Insulin-Secreting Cells
Male
Organ Size
Osteochondrodysplasias
Pedigree
Phenotype
Testis
Urogenital Abnormalities