YIPF5 mutations cause neonatal diabetes and microcephaly: progress for precision medicine and mechanistic understanding Toni I. Pollin, Simeon I. Taylor J Clin Invest. 2020. https://doi.org/10.1172/JCI142364. Commentary Identifying genes that result in monogenic diabetes can provide insights that can build a scientific foundation for precision medicine. At present, nearly 20% of neonatal diabetes cases have unknown causes. In this issue of the JCI, De Franco and Lytrivi et al. sequenced the genome of two probands with a rare neonatal diabetes subtype that also associated with microcephaly and epilepsy. The authors revealed mutations in the YIPF5 gene. YIPF5 resides in the Golgi apparatus and is thought to play a critical role in vesicular trafficking. Notably, disrupting YIPF5 in β cell–based models induced ER stress signaling and resulted in the accumulation of intracellular proinsulin. We believe that utilizing registries and biobanks to reveal other monogenic atypical forms of diabetes is an important approach to gaining insight and suggest that an insulin sensitizer may alleviate ER stress associated with YIPF5 disruption by decreasing the demand for insulin secretion. Find the latest version: https://jci.me/142364/pdf The Journal of Clinical Investigation COMMENTARY YIPF5 mutations cause neonatal diabetes and microcephaly: progress for precision medicine and mechanistic understanding Toni I. Pollin and Simeon I. Taylor Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. were described in the 1970s (11, 12), and shown in the 1980s to be caused by muta- Identifying genes that result in monogenic diabetes can provide insights that tions in the insulin receptor gene (13–15). can build a scientific foundation for precision medicine. At present, nearly 20% of neonatal diabetes cases have unknown causes. In this issue of the Precision medicine JCI, De Franco and Lytrivi et al. sequenced the genome of two probands with opportunities a rare neonatal diabetes subtype that also associated with microcephaly and As emphasized by Hattersley and Patel epilepsy. The authors revealed mutations in the YIPF5 gene. YIPF5 resides (16), precision medicine has at least three in the Golgi apparatus and is thought to play a critical role in vesicular important benefits: (a) optimizing choice trafficking. Notably, disrupting YIPF5 in β cell–based models induced ER of medications, (b) enhanced ability to stress signaling and resulted in the accumulation of intracellular proinsulin. predict patients’ clinical courses, and (c) We believe that utilizing registries and biobanks to reveal other monogenic enabling early diagnosis through genetic atypical forms of diabetes is an important approach to gaining insight and technology. For example, nine years after suggest that an insulin sensitizer may alleviate ER stress associated with the identification of HNF1A as the MODY3 YIPF5 disruption by decreasing the demand for insulin secretion. gene, Hattersley and colleagues reported that individuals harboring HNF1A muta- tions and previously diagnosed with type 1 diabetes could switch from insulin injec- tions to low-dose oral sulfonylureas with- Monogenic diabetes genes by a lower degree of severity and the lack out loss of glycemic control (17). As this Precision medicine for diabetes is often of a requirement for insulin treatment. group at the University of Exeter led the said to be on the horizon. However, as The age of onset sets MODY apart from way in implementation, they and others noted in the recent joint American Dia- maturity-onset diabetes (now known as continued to discover monogenic diabetes betes Association (ADA)/European Asso- type 2 diabetes). MODY’s distinct Mende- genes. They made another breakthrough ciation for the Study of Diabetes (EASD) lian inheritance pattern sets it apart from discovery in 2004 by finding that 10 of Precision Medicine in Diabetes Initiative both types (3). 29 patients with the rare condition of neo- (PMDI) consensus report (1), in some The first three MODY genes were natal diabetes had activating mutations instances the horizon stretches back sev- identified as GCK (MODY2) in 1992 (4), in the KCNJ11 gene encoding the Kir6.2 eral decades. The existence of monogenic HNF4A (MODY1) in 1996 (5), and HNF1A subunit of the ATP-sensitive potassium forms of diabetes has long been known. (MODY3) in 1996 (6). A separate stream of channel (18). Just two years later they In 1974, Tattersall noted “mild familial research identified several monogenic dia- established that high-dose oral sulfony- diabetes with dominant inheritance” (2) betes syndromes characterized by severe lureas, instead of insulin injections, could in some families, and shortly thereafter insulin resistance. Although generalized successfully treat most of the patients with Tattersall together with Fajans coined lipodystrophy was described in the 1950s (7, KCNJ11 mutations (19). the term “maturity onset diabetes of the 8), it would take another forty-plus years to Fast-forward to today. De Franco and young (MODY).” MODY is distinguished identity two disease genes: AGPAT2 (9) and Lytrivi et al. (20) note in this issue of the clinically from classical juvenile-onset BSCL2 (10). In addition, several syndromes JCI that, prior to the current work, 30 neo- diabetes (now known as type 1 diabetes) of insulin-resistant diabetes syndromes natal diabetes genes had been identified — accounting for 82% of cases. Variants in some of these genes cause extrapancreatic Related Article: https://doi.org/10.1172/JCI141455 syndromic features, including neurolog- ical features with 11 of the genes. Identi- Conflict of interest: TIP receives partial research funding from a grant to the University of Maryland, Baltimore, by the fication of these rarer neonatal subtypes Regeneron Genetics Center. SIT serves as a paid consultant to Ionis Pharmaceuticals and is listed as an inventor on a yields precision medicine opportunities methods of use patent, titled “Use of leptin for treating human lipoatrophy and method of determining predisposition to as well; for example, FOXP3 mutations said treatment” (US 7,183,254 B2). Copyright: © 2020, American Society for Clinical Investigation. in neonatal diabetes reveal an underlying Reference information: J Clin Invest. https://doi.org/10.1172/JCI142364. polyendocrinopathy in which early treat- jci.org 1 COMMENTARY The Journal of Clinical Investigation ment with a bone marrow transplant can group, based at the University of Maryland two Rab-like GTPases as bait (Ypt1 and prevent otherwise often fatal gastrointes- School of Medicine, brings experts togeth- Ypt31) (25). In a follow-up two-hybrid tinal enteropathy (21). Precision medicine er to pool clinical data and to develop and screen, Yif1p was discovered as a Yip1p-in- has also led to an innovative treatment for implement disease- as well as gene-spe- teracting protein (26). Functional studies generalized lipodystrophy. Metreleptin cific variant classification rules (24). demonstrated that Yip1p and Yif1p form provides life-changing efficacy to patients Exome sequencing is challenging a heterodimer, which plays a critical role with generalized lipodystrophy (22) and because of the volume of data generated in vesicle trafficking from the endoplas- has received regulatory approval as a new and consequent magnified difficulty of mic reticulum (ER) to the cis-Golgi; Rab- drug specifically indicated to treat that distinguishing benign from causal vari- like proteins play a downstream role in orphan disease. ation. The risk of false positives is high. the process (26). Seven members of the The Exeter group has a strong diag- One must go about it in a both systematic Yip1 domain family have been identified nostic program for monogenic diabetes. and open-minded, exploratory manner. in humans: YIPF1, YIPF2, YIPF3, YIPF4, Patients evaluated throughout the Unit- It is helpful to define a specific pheno- YIPF5, YIPF6, and YIPF7 (27). YIPF5 is ed Kingdom and worldwide undergo type, study multiple affected individuals, located in the early Golgi intermediate next-generation sequencing on a grow- and suspect a specific inheritance pat- compartment (ERGIC) and is viewed as the ing panel currently containing 71 known tern. In De Franco and Lytrivi et al. (20), ortholog of yeast Yip1p (28). YIPF5-con- or putative monogenic diabetes genes, the authors met these requirements by taining complexes are believed to play a where a subset is analyzed guided by sequencing two unrelated individuals critical role in trafficking of COPII-coated clinical information. A well-curated list with the specific constellation of neonatal vesicles from the ER to the cis-Golgi (27). of these genes is provided on the Diabe- diabetes, seizures, and severe microceph- Other YIPF family members are found in tesGenes website (https://www.diabetes- aly. Both were born to first-cousin pairs, characteristic locations in the ER or Golgi genes.org/). This diagnostic program is increasing the likelihood of autosomal and are also believed to function in vesicle currently the most cost-effective method recessive inheritance due to homozy- transport (27, 29). for achieving a clinical genetic diagnosis gous inheritance in each case of a vari- Proinsulin is synthesized by ribosomes and optimally captures the specific genes ant shared by the related parents. This in the rough ER and transported through involved. However, this routine approach approach allowed