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A Novel Syndrome With Short Stature, Mandibular Hypoplasia, and Osteoporosis May Be Associated With a PRRT3 Variant.

ABSTRACT: Context:Despite considerable progress in elucidating the molecular basis of various progeroid syndromes, some rare patients remain unexplained. Objective:To elucidate molecular genetic basis of a novel autosomal recessive progeroid syndrome. Participants:A 24-year-old male and his 18-year-old sister with short stature, mandibular hypoplasia, pointed nose, shrill voice, severe osteoporosis, and short eyebrows and their unaffected siblings and parents belonging to a consanguineous Arab family. Results:Using exome and Sanger sequencing, we report a novel homozygous p.Glu394Lys disease-causing variant in proline-rich transmembrane protein 3 (PRRT3). PRRT3 belongs to the family of proline-rich proteins containing several repeats of a short proline-rich sequence, but its function remains to be determined. Preliminary observations showing colocalization of Prrt3 and synaptophysin support its role in vesicle exocytosis. Consistent with the highest messenger ribonucleic acid expression of PRRT3 in the pituitary, both the patients had mild growth hormone deficiency but had near normal reproductive development. Conclusions:We conclude that the homozygous p.Glu394Lys variant in PRRT3 may be associated with a novel autosomal recessive, progeroid syndrome with short stature, mandibular hypoplasia, osteoporosis, short eyebrows, and mild growth hormone (GH) deficiency. Our findings extend the spectrum of progeroid syndromes and elucidate important functions of PRRT3 in human biology, including secretion of GH from the pituitary.

SUBMITTER: Garg A

PROVIDER: S-EPMC7417871 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A Novel Syndrome With Short Stature, Mandibular Hypoplasia, and Osteoporosis May Be Associated With a <i>PRRT3</i> Variant.

Garg Abhimanyu A El-Shanti Hatem H Xing Chao C Zhou Zhengyang Z Abujbara Mousa M Al-Rashed Khadeja K El-Khateeb Mohammed M Ajlouni Kamel K Agarwal Anil K AK

Journal of the Endocrine Society 20200708 8

<h4>Context</h4>Despite considerable progress in elucidating the molecular basis of various progeroid syndromes, some rare patients remain unexplained.<h4>Objective</h4>To elucidate molecular genetic basis of a novel autosomal recessive progeroid syndrome.<h4>Participants</h4>A 24-year-old male and his 18-year-old sister with short stature, mandibular hypoplasia, pointed nose, shrill voice, severe osteoporosis, and short eyebrows and their unaffected siblings and parents belonging to a consangui ...[more]

PMID: 32803092

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Project description:ContextCDKN1C, 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.ObjectiveTo investigate the genetic basis for a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.Design, setting, and participantsGenomic 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.ResultsThe 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.ConclusionsWe 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.

Project description:Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called 'ciliopathies' and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population.Twenty-three patients with ALMS (age, 1-52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone-releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic-pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized.The length-for-age measurements from birth to 36 months showed normal growth with most values falling within -0·67 SDS to +1·28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16-20 years; mean SDS, -2·22 ± 1·16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154·7 ± 10·6 cm vs 162·9 ± 4·8 cm, P = 0·009) and a mild increase in BMI (Kg/m(2) ) (27·8 ± 4·8 vs 24·1 ± 2·5, P = 0·007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11·9 ± 6·9 ?g/l vs 86·1 ± 33·2 ?g/l, P < 0·0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149·7 ± 6·2 cm vs 161·9 ± 9·2 cm, P = 0·04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases.Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.

Dataset Information

A Novel Syndrome With Short Stature, Mandibular Hypoplasia, and Osteoporosis May Be Associated With a PRRT3 Variant.

Publications

A Novel Syndrome With Short Stature, Mandibular Hypoplasia, and Osteoporosis May Be Associated With a <i>PRRT3</i> Variant.

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